ABCMdb

ABCA1 p.Arg230Cys

Predicted by SNAP2:	A: D (53%), C: D (85%), D: D (85%), E: D (75%), F: D (59%), G: D (71%), H: N (78%), I: N (61%), K: N (57%), L: N (78%), M: N (61%), N: D (53%), P: D (80%), Q: D (85%), S: N (53%), T: N (57%), V: N (53%), W: D (95%), Y: N (72%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] miR-33a modulates ABCA1 expression, cholesterol ac... Diabetes. 2012 Mar;61(3):653-8. Epub 2012 Feb 7. Wijesekara N, Zhang LH, Kang MH, Abraham T, Bhattacharjee A, Warnock GL, Verchere CB, Hayden MR
miR-33a modulates ABCA1 expression, cholesterol accumulation, and insulin secretion in pancreatic islets.
Diabetes. 2012 Mar;61(3):653-8. Epub 2012 Feb 7., [PMID:22315319]

Abstract [show]
Changes in cellular cholesterol affect insulin secretion, and beta-cell-specific deletion or loss-of-function mutations in the cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) result in impaired glucose tolerance and beta-cell dysfunction. Upregulation of ABCA1 expression may therefore be beneficial for the maintenance of normal islet function in diabetes. Studies suggest that microRNA-33a (miR-33a) expression inversely correlates with ABCA1 expression in hepatocytes and macrophages. We examined whether miR-33a regulates ABCA1 expression in pancreatic islets, thereby affecting cholesterol accumulation and insulin secretion. Adenoviral miR-33a overexpression in human or mouse islets reduced ABCA1 expression, decreased glucose-stimulated insulin secretion, and increased cholesterol levels. The miR-33a-induced reduction in insulin secretion was rescued by cholesterol depletion by methyl-beta-cyclodextrin or mevastatin. Inhibition of miR-33a expression in apolipoprotein E knockout islets and ABCA1 overexpression in beta-cell-specific ABCA1 knockout islets rescued normal insulin secretion and reduced islet cholesterol. These findings confirm the critical role of beta-cell ABCA1 in islet cholesterol homeostasis and beta-cell function and highlight modulation of beta-cell miR-33a expression as a means to influence insulin secretion.

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12 An R230C variant is also associated with early onset type 2 diabetes in the Mexican population (4). Login to comment

[hide] Carbohydrate intake modulates the effect of the AB... J Nutr. 2012 Feb;142(2):278-83. Epub 2011 Dec 21. Romero-Hidalgo S, Villarreal-Molina T, Gonzalez-Barrios JA, Canizales-Quinteros S, Rodriguez-Arellano ME, Yanez-Velazco LB, Bernal-Alcantara DA, Villa AR, Antuna-Puente B, Acuna-Alonzo V, Merino-Garcia JL, Moreno-Sandoval HN, Carnevale A
Carbohydrate intake modulates the effect of the ABCA1-R230C variant on HDL cholesterol concentrations in premenopausal women.
J Nutr. 2012 Feb;142(2):278-83. Epub 2011 Dec 21., [PMID:22190032]

Abstract [show]
The R230C variant of the ATP-binding cassette transporter A1 (ABCA1) gene has been consistently associated with decreased HDL-cholesterol (HDL-C) concentrations in several studies in the Mexican mestizo population. However, information on how diet composition modifies the effect of the ABCA1-R230C variant on HDL-C concentrations is very scarce. The aim of the present study was to analyze whether the effect of ABCA1-R230C on HDL-C concentrations is modulated by dietary factors in a nationwide population sample of 3591 adults from the National Health and Nutrition Survey conducted by the State's Employees' Social Security and Social Services Institute. All participants answered a validated questionnaire to assess health status and weekly food consumption. Fasting blood samples were drawn for biochemical analysis and DNA extraction, and the ABCA1-R230C variant was genotyped using TaqMan assays. Statistical analyses consisted of simple linear and multiple regression modeling adjusting for age, BMI, smoking, and alcohol consumption. The overall C risk allele frequency was 9.3% and the variant was significantly associated with low HDL-C concentrations in both sexes. A significant negative correlation between carbohydrate consumption and HDL-C concentrations was observed in women bearing the R230C variant (P = 0.021) and a significant gene-diet interaction was found only in premenopausal women (P = 0.037). In conclusion, the effect of the ABCA1-R230C gene variant on HDL-C concentrations is modulated by carbohydrate intake in premenopausal women. This finding may help design optimized dietary interventions according to sex and ABCA1-R230C genotype.

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1 Adolfo Lo´pez Mateos", and 8 Medical Direction, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico City, Mexico; 9 School of Chemistry, and 10 Department of Public Health, School of Medicine, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico; 11 Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Mexico City, Mexico; 12 Department of Research in Biochemistry, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; and 13 Molecular Genetics Laboratory, Escuela Nacional de Antropologı´a e Historia, Mexico City, Mexico Abstract The R230C variant of the ATP-binding cassette transporter A1 (ABCA1) gene has been consistently associated with decreased HDL-cholesterol (HDL-C) concentrations in several studies in the Mexican mestizo population. Login to comment
2 However, information on how diet composition modifies the effect of the ABCA1-R230C variant on HDL-C concentrations is very scarce. Login to comment
3 The aim of the present study was to analyze whether the effect of ABCA1-R230C on HDL-C concentrations is modulated by dietary factors in a nationwide population sample of 3591 adults from the National Health and Nutrition Survey conducted by the State`s Employees` Social Security and Social Services Institute. Login to comment
4 All participants answered a validated questionnaire to assess health status and weekly food consumption. Fasting blood samples were drawn for biochemical analysis and DNA extraction, and the ABCA1-R230C variant was genotyped using TaqMan assays. Login to comment
7 A significant negative correlation between carbohydrate consumption and HDL-C concentrations was observed in women bearing the R230C variant (P = 0.021) and a significant gene-diet interaction was found only in premenopausal women (P = 0.037). Login to comment
8 In conclusion, the effect of the ABCA1-R230C gene variant on HDL-C concentrations is modulated by carbohydrate intake in premenopausal women. Login to comment
9 This finding may help design optimized dietary interventions according to sex and ABCA1-R230C genotype. Login to comment
14 The R230C-ABCA1 gene variant was recently found to be private to the Americas and strongly associated with low HDL-C in Mexican mestizos and Native American populations (19-23). Login to comment
34 However, information on how diet composition modifies the effect of the ABCA1-R230C variant on HDL-C concentrations is very scarce. Login to comment
35 To date, there is only one report where hyperlipidemic individuals carrying the R230C risk allele showed a better HDL-C concentration response to a specific dietary intervention (low-saturated fat diet plus 25 g soy protein and 15 g soluble fiber) (28). Login to comment
36 The purpose of the present study was to analyze whether specific diet components modulate the effect of the ABCA1-R230C variant on HDL-C plasma concentrations to provide the bases for optimized dietary interventions. Login to comment
58 The R230C variant (rs9282541) was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System, Applied Biosystems). Login to comment
66 ANCOVA was used to determine associations between the R230C variant and metabolic variables, adjusting for age, BMI, smoking, and alcohol consumption. Login to comment
67 Simple linear regression models were built to study the effect of diet components on HDL-C concentrations stratified by sex and genotype, and multiple linear regression models were used to assess the interaction between the proportion of dietary carbohydrates and the R230C polymorphism on HDL-C concentrations, adjusting for the variables mentioned above. Login to comment
72 The C risk allele frequency was 9.3% in the TABLE 1 Anthropometric and serum biochemical measurements, lifestyle characteristics, and genotype distribution of the study participants stratified by sex1 Men (n = 1160) Women2 (n = 2431) Age, y 48.3 6 14.2 45.9 6 12.5b Anthropometric variables BMI, kg/m2 28.5 6 4.3 28.3 6 5.1 Weight, kg 80.1 6 15.0 68.7 6 14.0b Height, cm 167.6 6 7.6 155.8 6 6.9b Waist, cm 98.6 6 11.5 91.2 6 13.2b Metabolic variables Total-C, mmol/L 5.5 6 1.3 5.4 6 1.1 HDL-C, mmol/L 1.0 6 0.2 1.2 6 0.4b LDL-C, mmol/L 3.4 6 0.9 3.4 6 0.9 TG, mmol/L 2.8 6 3.0 1.9 6 1.3b Glucose, mmol/L 61.2 6 26.3 56.3 6 20.9b Systolic blood pressure, mm Hg 130.3 6 16.1 122.2 6 16.5b Diastolic blood pressure, mm Hg 81.9 6 10.3 77.3 6 10.6b Dietary intake Total energy, kcal/d 2660 6 913 2220 6 804b Proteins, % energy 13.5 6 3.2 14.2 6 3.3b Proteins, g/d 87.9 6 31.1 77.3 6 28.8b Carbohydrates, % energy 55.3 6 9.3 57.6 6 8.3b Carbohydrates, g/d 363 6 126 318 6 122b Fats, % energy 28.4 6 6.3 29.4 6 6.3b Fats, g/d 84.2 6 34.7 73.2 6 33.3b Other characteristics Alcohol consumers, n (%) 986 (85.2) 1294 (53.5)b Daily, n (%) 23 (2.3) 10 (0.8) Weekly, n (%) 270 (27.4) 102 (7.9) Monthly, n (%) 122 (12.4) 82 (6.3) Occasionally, n (%) 571 (57.9) 1100 (85.0) Physical activity, h/wk 6.0 6 10.7 5.6 6 9.8 Daily smokers, n (%) 276 (23.8) 330 (13.6)b Overweight, n (%) 536 (46.7) 996 (41.6)a Obesity, n (%) 362 (31.5) 731 (30.6) ABCA1-R230C variant, n (%) RR 949 (81.8) 2010 (82.7) RC 202 (17.4) 398 (16.4) CC 9 (0.8) 23 (0.9) 1 Values are expressed as mean 6 SD or n (%). Login to comment
76 Association of ABCA1-R230C with metabolic traits. Login to comment
86 Predicted values were calculated from regression models containing the ABCA1-R230C variant, carbohydrate intake, and the interaction term, adjusted for age, BMI, tobacco smoking, and alcohol consumption (Fig. 4). Login to comment
89 Discussion The R230C variant of the ABCA1 gene is of particular interest because of its epidemiological implications; it is frequent and private to Native American and descendant populations, it has been consistently associated with low HDL-C concentrations in various reports (19,21-23) including the present study, and this variant is known to have a functional effect, decreasing cholesterol efflux in vitro by ~30% (22). Login to comment
91 The highest risk allele frequency was observed in the southern states (11.2%) in accordance with the higher Native American component of these populations and the Amerindian origin of the R230C variant (22,32). Login to comment
93 TABLE 2 Association between ABCA1-R230C polymorphism and serum lipid concentrations stratified by sex1 RR RC CC P2 Men n 766 158 8 Total-C, mmol/L 5.43 (5.31-5.56) 5.08 (4.90-5.27) 5.25 (4.54-6.06) ,0.001 HDL-C, mmol/L 0.97 (0.94-0.99) 0.91 (0.88-0.95) 0.85 (0.72-1.01) 0.002 LDL-C, mmol/L 3.30 (3.18-3.41) 3.08 (2.91-3.25) 4.12 (3.17-5.35) 0.020 Women n 1769 348 22 Total-C, mmol/L 5.39 (5.32-5.45) 5.26 (5.15-5.38) 4.86 (4.49-5.26) 0.010 HDL-C, mmol/L 1.20 (1.18-1.22) 1.09 (1.06-1.12) 1.08 (0.98-1.20) ,0.001 LDL-C, mmol/L 3.30 (3.24-3.36) 3.26 (3.16-3.37) 3.10 (2.76-3.47) 0.328 1 Values are geometric means (95% CI). Login to comment
97 To date, all studies assessing the effect of the ABCA1-R230C variant on HDL-C concentrations in different populations have been consistent. Login to comment
98 As expected, the R230C variant was significantly associated with lower HDL-C concentrations in the ENSADER sample, although the effect of the variant was greater in women than in men. Login to comment
108 A sex-specific gene-diet interaction was observed in the present study, because the inverse correlation between carbohydrate intake and HDL-C concentrations was greater in women bearing the R230C variant, particularly in those with a premenopausal status. Login to comment
109 In contrast, the R230C variant and carbohydrate intake showed an independent, nonadditive effect in men. Login to comment
113 To our knowledge, this is the first study reporting a sex-specific interaction between any ABCA1 variant and carbohydrate intake on HDL-C concentrations, representing the first effort to evaluate gene-nutrient interactions for the ABCA1-R230C gene variant. Login to comment
190 Villarreal-Molina MT, Aguilar-Salinas CA, Rodrı´guez-Cruz M, Rian˜o D, Villalobos-Comparan M, Coral-Vazquez R, Menjivar M, Yescas- Gomez P, Ko¨nigsoerg-Fainstein M, Romero-Hidalgo S, et al. The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. Login to comment
199 Association of R230C ABCA1 gene variant with low C-HDL levels and abnormal HDL subclass distribution in Mexican school-aged children. Login to comment
206 The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study. Atherosclerosis. 2011;216:146-50. Login to comment
37 To date, there is only one report where hyperlipidemic individuals carrying the R230C risk allele showed a better HDL-C concentration response to a specific dietary intervention (low-saturated fat diet plus 25 g soy protein and 15 g soluble fiber) (28). Login to comment
38 The purpose of the present study was to analyze whether specific diet components modulate the effect of the ABCA1-R230C variant on HDL-C plasma concentrations to provide the bases for optimized dietary interventions. Login to comment
60 The R230C variant (rs9282541) was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System, Applied Biosystems). Login to comment
68 ANCOVA was used to determine associations between the R230C variant and metabolic variables, adjusting for age, BMI, smoking, and alcohol consumption. Login to comment
69 Simple linear regression models were built to study the effect of diet components on HDL-C concentrations stratified by sex and genotype, and multiple linear regression models were used to assess the interaction between the proportion of dietary carbohydrates and the R230C polymorphism on HDL-C concentrations, adjusting for the variables mentioned above. Login to comment
74 The C risk allele frequency was 9.3% in the TABLE 1 Anthropometric and serum biochemical measurements, lifestyle characteristics, and genotype distribution of the study participants stratified by sex1 Men (n = 1160) Women2 (n = 2431) Age, y 48.3 6 14.2 45.9 6 12.5b Anthropometric variables BMI, kg/m2 28.5 6 4.3 28.3 6 5.1 Weight, kg 80.1 6 15.0 68.7 6 14.0b Height, cm 167.6 6 7.6 155.8 6 6.9b Waist, cm 98.6 6 11.5 91.2 6 13.2b Metabolic variables Total-C, mmol/L 5.5 6 1.3 5.4 6 1.1 HDL-C, mmol/L 1.0 6 0.2 1.2 6 0.4b LDL-C, mmol/L 3.4 6 0.9 3.4 6 0.9 TG, mmol/L 2.8 6 3.0 1.9 6 1.3b Glucose, mmol/L 61.2 6 26.3 56.3 6 20.9b Systolic blood pressure, mm Hg 130.3 6 16.1 122.2 6 16.5b Diastolic blood pressure, mm Hg 81.9 6 10.3 77.3 6 10.6b Dietary intake Total energy, kcal/d 2660 6 913 2220 6 804b Proteins, % energy 13.5 6 3.2 14.2 6 3.3b Proteins, g/d 87.9 6 31.1 77.3 6 28.8b Carbohydrates, % energy 55.3 6 9.3 57.6 6 8.3b Carbohydrates, g/d 363 6 126 318 6 122b Fats, % energy 28.4 6 6.3 29.4 6 6.3b Fats, g/d 84.2 6 34.7 73.2 6 33.3b Other characteristics Alcohol consumers, n (%) 986 (85.2) 1294 (53.5)b Daily, n (%) 23 (2.3) 10 (0.8) Weekly, n (%) 270 (27.4) 102 (7.9) Monthly, n (%) 122 (12.4) 82 (6.3) Occasionally, n (%) 571 (57.9) 1100 (85.0) Physical activity, h/wk 6.0 6 10.7 5.6 6 9.8 Daily smokers, n (%) 276 (23.8) 330 (13.6)b Overweight, n (%) 536 (46.7) 996 (41.6)a Obesity, n (%) 362 (31.5) 731 (30.6) ABCA1-R230C variant, n (%) RR 949 (81.8) 2010 (82.7) RC 202 (17.4) 398 (16.4) CC 9 (0.8) 23 (0.9) 1 Values are expressed as mean 6 SD or n (%). Login to comment
79 Association of ABCA1-R230C with metabolic traits. Login to comment
90 Predicted values were calculated from regression models containing the ABCA1-R230C variant, carbohydrate intake, and the interaction term, adjusted for age, BMI, tobacco smoking, and alcohol consumption (Fig. 4). Login to comment
95 The highest risk allele frequency was observed in the southern states (11.2%) in accordance with the higher Native American component of these populations and the Amerindian origin of the R230C variant (22,32). Login to comment
101 To date, all studies assessing the effect of the ABCA1-R230C variant on HDL-C concentrations in different populations have been consistent. Login to comment
102 As expected, the R230C variant was significantly associated with lower HDL-C concentrations in the ENSADER sample, although the effect of the variant was greater in women than in men. Login to comment
112 A sex-specific gene-diet interaction was observed in the present study, because the inverse correlation between carbohydrate intake and HDL-C concentrations was greater in women bearing the R230C variant, particularly in those with a premenopausal status. Login to comment
117 To our knowledge, this is the first study reporting a sex-specific interaction between any ABCA1 variant and carbohydrate intake on HDL-C concentrations, representing the first effort to evaluate gene-nutrient interactions for the ABCA1-R230C gene variant. Login to comment
195 Villarreal-Molina MT, Aguilar-Salinas CA, Rodr &#b4;guez-Cruz M, Rian dc;o D, Villalobos-Comparan M, Coral-Vazquez R, Menjivar M, Yescas-Gomez P, Ko &#a8;nigsoerg-Fainstein M, Romero-Hidalgo S, et al. The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. Login to comment
204 Association of R230C ABCA1 gene variant with low C-HDL levels and abnormal HDL subclass distribution in Mexican school-aged children. Login to comment
211 The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study. Atherosclerosis. 2011;216:146-50. Login to comment

[hide] A dietary pattern including nopal, chia seed, soy ... J Nutr. 2012 Jan;142(1):64-9. Epub 2011 Nov 16. Guevara-Cruz M, Tovar AR, Aguilar-Salinas CA, Medina-Vera I, Gil-Zenteno L, Hernandez-Viveros I, Lopez-Romero P, Ordaz-Nava G, Canizales-Quinteros S, Guillen Pineda LE, Torres N
A dietary pattern including nopal, chia seed, soy protein, and oat reduces serum triglycerides and glucose intolerance in patients with metabolic syndrome.
J Nutr. 2012 Jan;142(1):64-9. Epub 2011 Nov 16., [PMID:22090467]

Abstract [show]
Metabolic syndrome (MetS) is a health problem throughout the world and is associated with cardiovascular disease and diabetes. Thus, the purpose of the present work was to evaluate the effects of a dietary pattern (DP; soy protein, nopal, chia seed, and oat) on the biochemical variables of MetS, the AUC for glucose and insulin, glucose intolerance (GI), the relationship of the presence of certain polymorphisms related to MetS, and the response to the DP. In this randomized trial, the participants consumed their habitual diet but reduced by 500 kcal for 2 wk. They were then assigned to the placebo (P; n = 35) or DP (n = 32) group and consumed the reduced energy diet plus the P or DP beverage (235 kcal) minus the energy provided by these for 2 mo. All participants had decreases in body weight (BW), BMI, and waist circumference during the 2-mo treatment (P < 0.0001); however, only the DP group had decreases in serum TG, C-reactive protein (CRP), and AUC for insulin and GI after a glucose tolerance test. Interestingly, participants in the DP group with MetS and the ABCA1 R230C variant had a greater decrease in BW and an increase in serum adiponectin concentration after 2 mo of dietary treatment than those with the ABCA1 R230R variant. The results from this study suggest that lifestyle interventions involving specific DP for the treatment of MetS could be more effective if local foods and genetic variations of the population are considered.

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5 Interestingly, participants in the DP group with MetS and the ABCA1 R230C variant had a greater decrease in BW and an increase in serum adiponectin concentration after 2 mo of dietary treatment than those with the ABCA1 R230R variant. Login to comment
36 In Mexico, the polymorphisms of genes that are highly associated with BMI and T2D are ABCA1 (R230C), TCF7L2 (rs7903146), PPARG (rs1801282), and IRS1 (rs1801278) (18-21). Login to comment
93 Single nucleotide polymorphisms of the ABCA1 R230C (rs9282541), ABCA1 R219K (rs2230806), TCF7L2 (rs7903146), PPARG (rs1801282), and IRS1 (rs1801278) genes were determined using PCR-based TaqMan allele discrimination assays (ABI Prism 7900 HT Sequence Detection System, Applied Biosystems) (30). Login to comment
100 The differences between the P and DP groups with respect to the ABCA1 R230C polymorphism were determined using multifactor ANOVA adjusted for BMI. When the main effects were identified by the initial analysis, post hoc analysis using Bonferroni correction was conducted. Login to comment
136 The number of participants with a specific genotype distribution (wild-type allele homozygote, variant heterozygote, variant homozygote) for each polymorphism was as follows: ABCA1 R230C (56, 11, 0,); ABCA1 R219K (37, 26, 4); TCF7L2 C/T (51,13,3); PPARG P12A (58 7,2,); and IRS1 G972R (59 7,1,). Login to comment
137 Allele frequencies (wild-type, variant) were as follows: ABCA1 R230C (91.8%, 8.2%); ABCA1 R219K (74.6%, 25.4%); TCF7L2 C/T (85.8%, 14.2%); PPARG P12A (91.8%, 8.2%); and IRS1 G972R (93.3%, 6.7%). Login to comment
138 Associations between ABCA1 R230C and anthropometric and biochemical variables. Login to comment
139 The decrease in BW in the participants in the DP group with the ABCA1 R230C variant was significantly greater (25.0 6 1.9 kg) than those with ABCA1 R230R variant (21.7 6 2 kg), and the increase in the serum adiponectin concentration in participants with the ABCA1 R230C variant (1.7 6 1.6 mg/L) was significantly greater than in those with the ABCA1 R230R variant (0.2 6 1.0 mg/L) after 2 mo. Login to comment
142 The ABCA1 R230C, ABCA1 R219K, TCF7L2 C/T, PPARG P12A, and IRS1 G972R polymorphisms were not related to the other clinical or biochemical variables or the dietary treatments (data not shown). Login to comment
153 The ABCA1 R230C variant was chosen for this study, because carriers of the ABCA1 R230C variant, which is exclusive to Native American individuals, is associated with low HDL concentrations, obesity, and T2D in the Mexican population (45). Login to comment
154 Previous studies have demonstrated that adults with the ABCA1 R230C polymorphism respond better to a cholesterol-lowering diet than those with the R230R genotype (46). Login to comment
158 Interestingly, in spite of the higher risk of developing obesity or diabetes by Mexican mestizos with the ABCA1 R230C polymorphism, the participants in this study with this polymorphism had a better response to the DP and showed additional beneficial effects such as a greater reduction in BW and a greater increase in serum adiponectin concentrations (Fig. 2) without differences in energy intake compared to the participants with the ABCA1 R230R genotype. Login to comment
160 Although these results are very encouraging, additional experiments must be conducted in a larger population of individuals with the ABCA1 R230C variant to confirm these effects. Login to comment
161 A possible explanation for the improved response to the dietary treatment by the participants with the ABCA1 R230C polymorphism could be because the C230 allele may have been necessary for survival in times of food shortages, allowing the conservation of cholesterol inside the cell. Login to comment
237 Whole-grain ready-to-eat oat FIGURE 2 Changes in BW (A) and serum adiponectin (B) in participants with MetS who consumed the DP or P for 2 mo with ABCA1 R230R or ABCA1 R230C genotypes. Login to comment
270 Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, Huer- tas-Vazquez A, Menjivar M, Romero-Hidalgo S, Wacher NH, et al. Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population. Login to comment
37 In Mexico, the polymorphisms of genes that are highly associated with BMI and T2D are ABCA1 (R230C), TCF7L2 (rs7903146), PPARG (rs1801282), and IRS1 (rs1801278) (1821). Login to comment
95 Single nucleotide polymorphisms of the ABCA1 R230C (rs9282541), ABCA1 R219K (rs2230806), TCF7L2 (rs7903146), PPARG (rs1801282), and IRS1 (rs1801278) genes were determined using PCR-based TaqMan allele discrimination assays (ABI Prism 7900 HT Sequence Detection System, Applied Biosystems) (30). Login to comment
102 The differences between the P and DP groups with respect to the ABCA1 R230C polymorphism were determined using multifactor ANOVA adjusted for BMI. When the main effects were identified by the initial analysis, post hoc analysis using Bonferroni correction was conducted. Login to comment
140 Associations between ABCA1 R230C and anthropometric and biochemical variables. Login to comment
141 The decrease in BW in the participants in the DP group with the ABCA1 R230C variant was significantly greater (25.0 6 1.9 kg) than those with ABCA1 R230R variant (21.7 6 2 kg), and the increase in the serum adiponectin concentration in participants with the ABCA1 R230C variant (1.7 6 1.6 mg/L) was significantly greater than in those with the ABCA1 R230R variant (0.2 6 1.0 mg/L) after 2 mo. Login to comment
144 The ABCA1 R230C, ABCA1 R219K, TCF7L2 C/T, PPARG P12A, and IRS1 G972R polymorphisms were not related to the other clinical or biochemical variables or the dietary treatments (data not shown). Login to comment
155 The ABCA1 R230C variant was chosen for this study, because carriers of the ABCA1 R230C variant, which is exclusive to Native American individuals, is associated with low HDL concentrations, obesity, and T2D in the Mexican population (45). Login to comment
156 Previous studies have demonstrated that adults with the ABCA1 R230C polymorphism respond better to a cholesterol-lowering diet than those with the R230R genotype (46). Login to comment
162 Although these results are very encouraging, additional experiments must be conducted in a larger population of individuals with the ABCA1 R230C variant to confirm these effects. Login to comment
163 A possible explanation for the improved response to the dietary treatment by the participants with the ABCA1 R230C polymorphism could be because the C230 allele may have been necessary for survival in times of food shortages, allowing the conservation of cholesterol inside the cell. Login to comment
238 Whole-grain ready-to-eat oat FIGURE 2 Changes in BW (A) and serum adiponectin (B) in participants with MetS who consumed the DP or P for 2 mo with ABCA1 R230R or ABCA1 R230C genotypes. Login to comment
271 Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, Huertas-Vazquez A, Menjivar M, Romero-Hidalgo S, Wacher NH, et al. Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population. Login to comment

[hide] Evolutionary responses to a constructed niche: anc... PLoS One. 2012;7(6):e38862. Epub 2012 Jun 21. Hunemeier T, Amorim CE, Azevedo S, Contini V, Acuna-Alonzo V, Rothhammer F, Dugoujon JM, Mazieres S, Barrantes R, Villarreal-Molina MT, Paixao-Cortes VR, Salzano FM, Canizales-Quinteros S, Ruiz-Linares A, Bortolini MC
Evolutionary responses to a constructed niche: ancient Mesoamericans as a model of gene-culture coevolution.
PLoS One. 2012;7(6):e38862. Epub 2012 Jun 21., [PMID:22768049]

Abstract [show]
Culture and genetics rely on two distinct but not isolated transmission systems. Cultural processes may change the human selective environment and thereby affect which individuals survive and reproduce. Here, we evaluated whether the modes of subsistence in Native American populations and the frequencies of the ABCA1*Arg230Cys polymorphism were correlated. Further, we examined whether the evolutionary consequences of the agriculturally constructed niche in Mesoamerica could be considered as a gene-culture coevolution model. For this purpose, we genotyped 229 individuals affiliated with 19 Native American populations and added data for 41 other Native American groups (n = 1905) to the analysis. In combination with the SNP cluster of a neutral region, this dataset was then used to unravel the scenario involved in 230Cys evolutionary history. The estimated age of 230Cys is compatible with its origin occurring in the American continent. The correlation of its frequencies with the archeological data on Zea pollen in Mesoamerica/Central America, the neutral coalescent simulations, and the F(ST)-based natural selection analysis suggest that maize domestication was the driving force in the increase in the frequencies of 230Cys in this region. These results may represent the first example of a gene-culture coevolution involving an autochthonous American allele.

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33 Other examples are related to the coevolution of genes and languages [19,20], but only two more recently reported examples might be associated with positive selection: (1) Tovo-Rodrigues et al. [21] investigated the distribution of D4 dopamine receptor (DRD4) alleles in several South Amerindian populations and found a significant difference in the allelic distributions between hunter-gatherers and agriculturalists, with an increase of the 7R allele among the former; and (2) Acun˜a-Alonzo et al. [22] showed that the 230Cys allele (Arg230Cys, rs9282541) of the ATP-binding cassette transporter A1 (ABCA1) gene, which was previously associated with low HDL-cholesterol levels and obesity-related comorbidities, was exclusively present in Native American and mestizo individuals. Login to comment
40 Here, we expand the investigations of the Arg230Cys polymorphism in Native Americans and integrate the thrifty genotype concept with the gene-culture coevolution process, considering the human ability to create new ecological niches that may lead to the selection of genetic variants. Login to comment
41 Materials and Methods (a) Populations New data for the Arg230Cys polymorphism were generated for 19 Amerindian populations (n = 229) from Meso/Central America and South America (Table 1). Login to comment
43 These new Arg230Cys data were then analyzed together with those of an earlier published report [22], providing a total of 1905 investigated individuals. Login to comment
52 (b) SNP Genotyping and Intra-and Inter-subdivision Structures The Arg230Cys polymorphism was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems). Login to comment
58 Population N1 Genotype frequency Allele frequency Country Geographical coordinates References Arg 230 Arg Arg 230 Cys Cys 230 Cys Arg230 230Cys Mesoamerican agriculturalist2 (1218) Yaqui 45 30 11 4 0.79 0.21 Mexico 27u 299 N 110u 409 W Acun˜a-Alonzo et al. (2010) Tarahumara 109 81 23 5 0.85 0.15 Mexico 26u 499 N 107u 049 W Acun˜a-Alonzo et al. (2010) Teenek 67 45 20 2 0.82 0.18 Mexico 21u 369 N 98u 589 W Acun˜a-Alonzo et al. (2010) Cora 123 62 51 10 0.71 0.29 Mexico 22u 39 N 104u 559 W Acun˜a-Alonzo et al. (2010) Purepecha 35 22 11 2 0.79 0.21 Mexico 19u 369 N 102u 149 W Acun˜a-Alonzo et al. (2010) Mazahua 83 68 15 0 0.91 0.09 Mexico 19u 269 N 100u 009 W Acun˜a-Alonzo et al. (2010) Mixe 19 15 4 0 0.89 0.11 Mexico 17u N 96uW Present study Mixtec 4 4 0 0 1.00 0.00 Mexico 17u N 97uW Present study Nahuatl 267 185 73 9 0.83 0.17 Mexico 19u 589 N 97u 379 W Acun˜a-Alonzo et al. (2010) Totonaco 113 86 24 3 0.87 0.13 Mexico 19u 579 N 97u 449 W Acun˜a-Alonzo et al. (2010) Otomı´es 42 35 7 0 0.92 0.08 Mexico 20u 289 N 99u 139 W Acun˜a-Alonzo et al. (2010) Zapotec 125 71 50 4 0.76 0.24 Mexico 17u149 N 96u149 W Present study; Acun˜a-Alonzo et al. (2010) Mayan 110 68 39 3 0.80 0.20 Mexico 20u139 N 90u289 W Acun˜a-Alonzo et al. (2010) Kaqchikel-Quiche 17 13 3 1 0.85 0.15 Guatemala 15u N 91uW Present study Cabecar 24 19 5 0 0.90 0.10 Costa Rica 9u 309 N 84uW Present study Guaymı´ 35 26 8 1 0.85 0.15 Costa Rica/ Panama´ 8u309 N 82u W Present study South American hunter-gatherer/forager2 (572) Parkatejeˆ (Gavia˜o) 78 65 12 1 0.91 0.09 Brazil 05u 039 S 48u 369 W Acun˜a-Alonzo et al. (2010) Jamamadi 26 26 0 0 1.00 0.00 Brazil 07u 159 S 66u 419 W Acun˜a-Alonzo et al. (2010) Mekranoti (Kayapo´) 25 24 1 0 0.98 0.02 Brazil 08u 409 S 54u W Acun˜a-Alonzo et al. (2010) Mura (Piraha˜) 18 11 6 1 0.78 0.22 Brazil 03u349 S 59u 129 W Acun˜a-Alonzo et al. (2010) Pacaa´s-Novos (Wari) 25 23 2 0 0.96 0.04 Brazil 11u 089 S 65u 059 W Acun˜a-Alonzo et al. (2010) Satere´-Mawe´ 25 20 4 1 0.88 0.12 Brazil 03u S 57u W Acun˜a-Alonzo et al. (2010) Apalaı´ 22 15 7 0 0.84 0.16 Brazil 01u209 N 54u409 W Acun˜a-Alonzo et al. (2010) Arara 24 15 9 0 0.81 0.19 Brazil 03u 309 S 54u109 W Acun˜a-Alonzo et al. (2010) Guarani 31 30 1 0 0.98 0.02 Brazil 25u 209 S 52u 309 W Present study; Acun˜a-Alonzo et al. (2010) Gorotire (Kayapo) 7 6 0 1 0.86 0.14 Brazil 07u 449 S 51u 109 W Acun˜a-Alonzo et al. (2010) Karitiana 20 20 0 0 1.00 0.00 Brazil 08u 459 S 63u 519 W Acun˜a-Alonzo et al. (2010) Xavante 21 10 9 2 0.69 0.31 Brazil 13u 209 S 51u 409 W Acun˜a-Alonzo et al. (2010) Xikrin (Kayapo) 17 16 1 0 0.97 0.03 Brazil 05u559 S 51u119 W Acun˜a-Alonzo et al. (2010) Yanomama 25 20 4 1 0.88 0.12 Brazil 02u30 9-04u309 N 64u W Acun˜a-Alonzo et al. (2010) Txukahamae (Kayapo) 30 26 4 0 0.93 0.07 Brazil 10u 209 S 53u 59 W Acun˜a-Alonzo et al. (2010) Tiriyo´ (Trio) 25 21 4 0 0.92 0.08 Brazil 01u 579 N 55u499 W Acun˜a-Alonzo et al. (2010) Ic¸ana River (Baniwa) 19 13 3 3 0.76 0.24 Brazil 01u N 67u 509 W Acun˜a-Alonzo et al. (2010) Kuben Kran Keng (Kayapo) 17 13 4 0 0.88 0.12 Brazil 08u109 S 58u89 W Acun˜a-Alonzo et al. (2010) Lengua 29 29 0 0 1.00 0.00 Paraguay 23u S 56u W Acun˜a-Alonzo et al. (2010) Ache (Guayaki) 23 23 0 0 1.00 0.00 Paraguay 23u S 58u W Acun˜a-Alonzo et al. (2010) Ayoreo 30 30 0 0 1.00 0.00 Paraguay 16-22u S 58-63u W Acun˜a-Alonzo et al. (2010) Zenu 4 4 0 0 1.00 0.00 Colombia 9u N 75u W Present study Kogi 7 7 0 0 1.00 0.00 Colombia 11u N 74u W Present study Ticuna 1 1 0 0 1.00 0.00 Colombia 3u 539 S 70uW Present study Embera 3 3 0 0 1.00 0.00 Colombia 7u N 76u W Present study Wayuu 17 15 2 0 0.94 0.06 Colombia 11u N 73u W Present study Palikur 3 1 2 0 0.67 0.33 French Guiana 4u N 51u 459 W Present study ,680,000 SNPs (Ruiz-Linares et al., unpublished data). Login to comment
83 Population N1 Genotype frequency Allele frequency Country Geographical coordinates References Arg 230 Arg Arg 230 Cys Cys 230 Cys Arg230 230Cys Andean agriculturalist2 (115) Mapuche 40 40 0 0 1.00 0.00 Chile 40u 309 S 69u 209 W Acun˜a-Alonzo et al. (2010) Aymara 16 16 0 0 1.00 0.00 Bolivia 16u309 S 68u99 W Present study Quechua 16 15 1 0 0.97 0.03 Bolivia 14u309 S 69u W Present study Aymara 22 20 2 0 0.95 0.05 Chile 22u S 70u W Present study Chilote 2 2 0 0 1.00 0.00 Chile 42u309 S 73u559 W Present study Hulliche 13 10 3 0 0.89 0.11 Chile 41u S 73u W Present study Ingano 6 5 1 0 0.92 0.08 Colombia 1u N 77u W Present study 1 Samples genotyped in present study = 229; 2 Caution is needed regarding the classification of these modes of subsistence, since they are not stable over time and may not be unique. Login to comment
140 Discussion We can now examine some hypotheses in an attempt to explain the results and to draw the evolutionary scenario associated with the pattern of diversity of the ABCA1* Arg230Cys polymorphism. Login to comment
167 In agreement with this historical scenario, the genetic variation in Arg230Cys presented a worse fit to neutrality than loci known to be neutral, indicating that selective mechanisms are necessary to explain the genetic diversity of Arg230Cys, especially when the Mesoamerican agriculturalist subdivision is considered in the analysis. Login to comment
177 Therefore, the significant role of random processes and/or more heterogeneous cultural and ecological scenarios makes it difficult to define a particular pattern associated with the Arg230Cys polymorphism in South American groups, a situation different from that in Mesoamerica. In conclusion, our analyses demonstrate for the first time a robust correlation between a constructed niche and a selected Native American autochthonous allele. Login to comment
259 Romero-Hidalgo S, Villarreal-Molina T, Gonza´lez-Barrios JA, Canizales- Quinteros S, Rodrı´guez-Arellano ME, et al. (2012) Carbohydrate intake modulates the effect of the ABCA1-R230C variant on HDL cholesterol concentrations in premenopausal women. Login to comment
34 Other examples are related to the coevolution of genes and languages [19,20], but only two more recently reported examples might be associated with positive selection: (1) Tovo-Rodrigues et al. [21] investigated the distribution of D4 dopamine receptor (DRD4) alleles in several South Amerindian populations and found a significant difference in the allelic distributions between hunter-gatherers and agriculturalists, with an increase of the 7R allele among the former; and (2) Acun dc;a-Alonzo et al. [22] showed that the 230Cys allele (Arg230Cys, rs9282541) of the ATP-binding cassette transporter A1 (ABCA1) gene, which was previously associated with low HDL-cholesterol levels and obesity-related comorbidities, was exclusively present in Native American and mestizo individuals. Login to comment
42 Materials and Methods (a) Populations New data for the Arg230Cys polymorphism were generated for 19 Amerindian populations (n = 229) from Meso/Central America and South America (Table 1). Login to comment
44 These new Arg230Cys data were then analyzed together with those of an earlier published report [22], providing a total of 1905 investigated individuals. Login to comment
53 (b) SNP Genotyping and Intra-and Inter-subdivision Structures The Arg230Cys polymorphism was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems). Login to comment
59 Population N1 Genotype frequency Allele frequency Country Geographical coordinates References Arg 230 Arg Arg 230 Cys Cys 230 Cys Arg230 230Cys Mesoamerican agriculturalist2 (1218) Yaqui 45 30 11 4 0.79 0.21 Mexico 27u 299 N 110u 409 W Acun dc;a-Alonzo et al. (2010) Tarahumara 109 81 23 5 0.85 0.15 Mexico 26u 499 N 107u 049 W Acun dc;a-Alonzo et al. (2010) Teenek 67 45 20 2 0.82 0.18 Mexico 21u 369 N 98u 589 W Acun dc;a-Alonzo et al. (2010) Cora 123 62 51 10 0.71 0.29 Mexico 22u 39 N 104u 559 W Acun dc;a-Alonzo et al. (2010) Purepecha 35 22 11 2 0.79 0.21 Mexico 19u 369 N 102u 149 W Acun dc;a-Alonzo et al. (2010) Mazahua 83 68 15 0 0.91 0.09 Mexico 19u 269 N 100u 009 W Acun dc;a-Alonzo et al. (2010) Mixe 19 15 4 0 0.89 0.11 Mexico 17u N 96uW Present study Mixtec 4 4 0 0 1.00 0.00 Mexico 17u N 97uW Present study Nahuatl 267 185 73 9 0.83 0.17 Mexico 19u 589 N 97u 379 W Acun dc;a-Alonzo et al. (2010) Totonaco 113 86 24 3 0.87 0.13 Mexico 19u 579 N 97u 449 W Acun dc;a-Alonzo et al. (2010) Otom &#b4;es 42 35 7 0 0.92 0.08 Mexico 20u 289 N 99u 139 W Acun dc;a-Alonzo et al. (2010) Zapotec 125 71 50 4 0.76 0.24 Mexico 17u149 N 96u149 W Present study; Acun dc;a-Alonzo et al. (2010) Mayan 110 68 39 3 0.80 0.20 Mexico 20u139 N 90u289 W Acun dc;a-Alonzo et al. (2010) Kaqchikel-Quiche 17 13 3 1 0.85 0.15 Guatemala 15u N 91uW Present study Cabecar 24 19 5 0 0.90 0.10 Costa Rica 9u 309 N 84uW Present study Guaym &#b4; 35 26 8 1 0.85 0.15 Costa Rica/ Panama &#b4; 8u309 N 82u W Present study South American hunter-gatherer/forager2 (572) Parkateje c6; (Gavia dc;o) 78 65 12 1 0.91 0.09 Brazil 05u 039 S 48u 369 W Acun dc;a-Alonzo et al. (2010) Jamamadi 26 26 0 0 1.00 0.00 Brazil 07u 159 S 66u 419 W Acun dc;a-Alonzo et al. (2010) Mekranoti (Kayapo &#b4;) 25 24 1 0 0.98 0.02 Brazil 08u 409 S 54u W Acun dc;a-Alonzo et al. (2010) Mura (Piraha dc;) 18 11 6 1 0.78 0.22 Brazil 03u349 S 59u 129 W Acun dc;a-Alonzo et al. (2010) Pacaa &#b4;s-Novos (Wari) 25 23 2 0 0.96 0.04 Brazil 11u 089 S 65u 059 W Acun dc;a-Alonzo et al. (2010) Satere &#b4;-Mawe &#b4; 25 20 4 1 0.88 0.12 Brazil 03u S 57u W Acun dc;a-Alonzo et al. (2010) Apala &#b4; 22 15 7 0 0.84 0.16 Brazil 01u209 N 54u409 W Acun dc;a-Alonzo et al. (2010) Arara 24 15 9 0 0.81 0.19 Brazil 03u 309 S 54u109 W Acun dc;a-Alonzo et al. (2010) Guarani 31 30 1 0 0.98 0.02 Brazil 25u 209 S 52u 309 W Present study; Acun dc;a-Alonzo et al. (2010) Gorotire (Kayapo) 7 6 0 1 0.86 0.14 Brazil 07u 449 S 51u 109 W Acun dc;a-Alonzo et al. (2010) Karitiana 20 20 0 0 1.00 0.00 Brazil 08u 459 S 63u 519 W Acun dc;a-Alonzo et al. (2010) Xavante 21 10 9 2 0.69 0.31 Brazil 13u 209 S 51u 409 W Acun dc;a-Alonzo et al. (2010) Xikrin (Kayapo) 17 16 1 0 0.97 0.03 Brazil 05u559 S 51u119 W Acun dc;a-Alonzo et al. (2010) Yanomama 25 20 4 1 0.88 0.12 Brazil 02u30 9-04u309 N 64u W Acun dc;a-Alonzo et al. (2010) Txukahamae (Kayapo) 30 26 4 0 0.93 0.07 Brazil 10u 209 S 53u 59 W Acun dc;a-Alonzo et al. (2010) Tiriyo &#b4; (Trio) 25 21 4 0 0.92 0.08 Brazil 01u 579 N 55u499 W Acun dc;a-Alonzo et al. (2010) Ic &#b8;ana River (Baniwa) 19 13 3 3 0.76 0.24 Brazil 01u N 67u 509 W Acun dc;a-Alonzo et al. (2010) Kuben Kran Keng (Kayapo) 17 13 4 0 0.88 0.12 Brazil 08u109 S 58u89 W Acun dc;a-Alonzo et al. (2010) Lengua 29 29 0 0 1.00 0.00 Paraguay 23u S 56u W Acun dc;a-Alonzo et al. (2010) Ache (Guayaki) 23 23 0 0 1.00 0.00 Paraguay 23u S 58u W Acun dc;a-Alonzo et al. (2010) Ayoreo 30 30 0 0 1.00 0.00 Paraguay 16-22u S 58-63u W Acun dc;a-Alonzo et al. (2010) Zenu 4 4 0 0 1.00 0.00 Colombia 9u N 75u W Present study Kogi 7 7 0 0 1.00 0.00 Colombia 11u N 74u W Present study Ticuna 1 1 0 0 1.00 0.00 Colombia 3u 539 S 70uW Present study Embera 3 3 0 0 1.00 0.00 Colombia 7u N 76u W Present study Wayuu 17 15 2 0 0.94 0.06 Colombia 11u N 73u W Present study Palikur 3 1 2 0 0.67 0.33 French Guiana 4u N 51u 459 W Present study ,680,000 SNPs (Ruiz-Linares et al., unpublished data). Login to comment
84 Population N1 Genotype frequency Allele frequency Country Geographical coordinates References Arg 230 Arg Arg 230 Cys Cys 230 Cys Arg230 230Cys Andean agriculturalist2 (115) Mapuche 40 40 0 0 1.00 0.00 Chile 40u 309 S 69u 209 W Acun dc;a-Alonzo et al. (2010) Aymara 16 16 0 0 1.00 0.00 Bolivia 16u309 S 68u99 W Present study Quechua 16 15 1 0 0.97 0.03 Bolivia 14u309 S 69u W Present study Aymara 22 20 2 0 0.95 0.05 Chile 22u S 70u W Present study Chilote 2 2 0 0 1.00 0.00 Chile 42u309 S 73u559 W Present study Hulliche 13 10 3 0 0.89 0.11 Chile 41u S 73u W Present study Ingano 6 5 1 0 0.92 0.08 Colombia 1u N 77u W Present study 1 Samples genotyped in present study = 229; 2 Caution is needed regarding the classification of these modes of subsistence, since they are not stable over time and may not be unique. Login to comment
141 Discussion We can now examine some hypotheses in an attempt to explain the results and to draw the evolutionary scenario associated with the pattern of diversity of the ABCA1* Arg230Cys polymorphism. Login to comment

[hide] The non-synonymous Arg230Cys variant (R230C) of th... Atherosclerosis. 2011 May;216(1):146-50. Epub 2011 Jan 22. Aguilar-Salinas CA, Canizales-Quinteros S, Rojas-Martinez R, Mehta R, Rodriguez-Guillen R, Ordonez-Sanchez ML, Riba L, Tusie-Luna MT
The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study.
Atherosclerosis. 2011 May;216(1):146-50. Epub 2011 Jan 22., [PMID:21315358]

Abstract [show]
OBJECTIVE: To search for an association between the non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 and low HDL cholesterol levels in a Mexican, population-based nation wide survey. METHODS: The 2000 National Health Survey is a cross sectional study that included individuals from 400 cities. All individuals who had a 9-12-h fasted blood sample and a DNA sample were selected (n = 1729). These cases were randomly distributed; no bias was detected for sex, education, region or socioeconomic status. The R230C variant was genotyped using TaqMan assays. RESULTS: In individuals with the R230C/C230C genotypes (39.03 mg/dl (36.63-41.43)) lower HDL-C levels (p < 0.001) were observed compared to those with the R230R genotype (44.7 mg/dl (43.31-46.24)). The difference remained significant after adjusting for gender, body mass index and waist circumference; the mean difference in HDL cholesterol levels between alleles was 5.73 +/- 1.4 mg/dl. The magnitude of the effect was significantly greater in males. The C230 allele of ABCA1 was associated with an increased risk for hypoalphalipoproteinemia (OR 1.66 (95%CI 1.08-2.54), p < 0.05). The population attributable risk (PAR) for having hypoalphalipoproteinemia of the C230 allele of the ABCA1, after considering the confounding effect of waist circumference and gender, was 12.2% (95%CI 1.4-24.2%). CONCLUSION: The non-synonymous Arg230Cys variant of ABCA1 is associated with low levels of HDL cholesterol levels in Mexican adults. The HDL cholesterol lowering effect of the variant is greater in males. The size of the effect is greater compared to that reported for other ABCA1 variants.

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0 Atherosclerosis 216 (2011) 146-150 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: A population based nation wide study Carlos A. Aguilar-Salinasa,* , Samuel Canizales-Quinterosb , Rosalba Rojas-Martínezc , Roopa Mehtaa , Rosario Rodriguez-Guillénb , María Luisa Ordo˜nez-Sanchezb , Laura Ribab , María Teresa Tusié-Lunab a Departamento de Endocrinología y Metabolismo del Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Mexico14000 D.F., Mexico b Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, México D.F., Mexico c Instituto Nacional de Salud Publica, Cuernavaca, Mor., Mexico a r t i c l e i n f o Article history: Received 7 August 2010 Received in revised form 24 September 2010 Accepted 5 October 2010 Available online 22 January 2011 Keywords: High density lipoproteins ABCA1 Mexico Native Americans a b s t r a c t Objective: To search for an association between the non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 and low HDL cholesterol levels in a Mexican, population-based nation wide survey. Login to comment
4 The R230C variant was genotyped using TaqMan assays. Login to comment
5 Results: In individuals with the R230C/C230C genotypes (39.03 mg/dl (36.63-41.43)) lower HDL-C levels (p < 0.001) were observed compared to those with the R230R genotype (44.7 mg/dl (43.31-46.24)). Login to comment
10 Conclusion: The non-synonymous Arg230Cys variant of ABCA1 is associated with low levels of HDL cholesterol levels in Mexican adults. Login to comment
18 This is the case for the non-synonymous Arg230Cys variant (R230C, rs9282541) of the ATP-binding cassette transporter A1 (ABCA1) gene in Amerindian populations. Login to comment
25 The R230C variant was strongly associated with hypoalphalipoproteinemia in two different Mexican clinic-based cohorts [2,5]. Login to comment
26 The R230C/C230C genotypes were significantly more frequent in the low HDL-C (≤10 percentile of the Mexican population) than in the high HDL-C group (≥90 percentile) (45% vs. 2.9%, p = 0.00006, p = 0.0005 after adjusting for admixture). Login to comment
28 The R230C variant decreases the activity of the ABCA1 transporter in vitro by 30% [3]. Login to comment
31 In this report we extend our observations and confirm the association between the R230C variant of the ABCA1 and low HDL 0021-9150/$ - see front matter (c) 2011 Elsevier Ireland Ltd. All rights reserved. Login to comment
111 Discussion Our data confirms the association between the non-synonymous Arg230Cys variant (R230C, rs9282541) of the ATP-binding cassette transporter A1 gene and hypoalphalipoproteinemia. Login to comment
130 The populations sampled have generally been com- Table 2 The effect of the R230C/C230C of ATP-binding cassette transporter A1 gene on the HDL cholesterol concentration is greater in males. Login to comment
131 R230R R230C C230C Absolute difference between C230 and R230R Men HDL cholesterol 42.2(40.6-43.8) 34.8(30.8-38.8)* 31.6(20.6-42.6)* -7.50 ± 2.2* HDL cholesterol adjusted for body mass index 42.2(40.61-43.85) 34.8(30.9-38.7)* 31.4(20.3-42.5)* -7.46 ± 2.1* HDL cholesterol adjusted for waist circumference 42.1(40.5-43.8) 34.9(30.9-41.3)* 30.7(20.2-41.3)* -7.33 ± 2.1* HDL cholesterol adjusted for waist circumference and body mass index 42.1(40.5-43.8) 34.9(30.9-38.8)* 30.7(20.1-41.3)* -7.34 ± 2.1* Women HDL cholesterol 47.2(45.1-49.3) 42.8(41.2-44.3)* 40.9(37.2-44.6)* -4.64 ± 1.0* HDL cholesterol adjusted for body mass index 47.2(45.1-49.3) 42.8(41.2-44.3)* 40.9(37.2-44.6)* -4.61 ± 1.0* HDL cholesterol adjusted for waist circumference 46.8(44.7-48.9) 42.5(41.0-44.1)* 42.1(38.3-45.7)* -4.33 ± 1.0* HDL cholesterol adjusted for waist circumference and body mass index 46.8(44.7-48.9) 42.5(41.0-44.1)* 42.0(38.3-45.7)* -4.34 ± 1.0* Data are medians (95%CI) or medians ± standard error. Login to comment
132 * p-Value < 0.001 comparing R230C or C230C vs. R230R. Login to comment
139 The Arg230Cys variant of the ABCA1 is a population-specific allele that has been shown to be associated with low HDL cholesterol levels in three case/control studies [2,4] and in a genome wide association study [21]. Login to comment
144 The R230C variant decreases the activity of the ABCA1 transporter in vitro by 30%. Login to comment
146 In addition, the proportion of larger HDL-C particles is smaller and the proportion of smaller HDL-C particles increases in R230C/C230C compared to R230R individuals [6]. Login to comment

[hide] Type 2 diabetes is associated with reduced ATP-bin... PLoS One. 2011;6(7):e22142. Epub 2011 Jul 27. Patel DC, Albrecht C, Pavitt D, Paul V, Pourreyron C, Newman SP, Godsland IF, Valabhji J, Johnston DG
Type 2 diabetes is associated with reduced ATP-binding cassette transporter A1 gene expression, protein and function.
PLoS One. 2011;6(7):e22142. Epub 2011 Jul 27., [PMID:21829447]

Abstract [show]
OBJECTIVE: Increasing plasma glucose levels are associated with increasing risk of vascular disease. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT). We studied the influence of plasma glucose on expression and function of a key mediator in RCT, the ATP binding cassette transporter-A1 (ABCA1) and expression of its regulators, liver X receptor-alpha (LXRalpha) and peroxisome proliferator-activated receptor-gamma (PPARgamma). METHODS AND RESULTS: Leukocyte ABCA1, LXRalpha and PPARgamma expression was measured by polymerase chain reaction in 63 men with varying degrees of glucose homeostasis. ABCA1 protein concentrations were measured in leukocytes. In a sub-group of 25 men, ABCA1 function was quantified as apolipoprotein-A1-mediated cholesterol efflux from 2-3 week cultured skin fibroblasts. Leukocyte ABCA1 expression correlated negatively with circulating HbA1c and glucose (rho = -0.41, p<0.001; rho = -0.34, p = 0.006 respectively) and was reduced in Type 2 diabetes (T2DM) (p = 0.03). Leukocyte ABCA1 protein was lower in T2DM (p = 0.03) and positively associated with plasma HDL cholesterol (HDL-C) (rho = 0.34, p = 0.02). Apolipoprotein-A1-mediated cholesterol efflux correlated negatively with fasting glucose (rho = -0.50, p = 0.01) and positively with HDL-C (rho = 0.41, p = 0.02). It was reduced in T2DM compared with controls (p = 0.04). These relationships were independent of LXRalpha and PPARgamma expression. CONCLUSIONS: ABCA1 expression and protein concentrations in leukocytes, as well as function in cultured skin fibroblasts, are reduced in T2DM. ABCA1 protein concentration and function are associated with HDL-C levels. These findings indicate a glycaemia-related, persistent disruption of a key component of RCT.

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361 Villarreal-Molina MT, Flores-Dorantes MT, Rellano-Campos O, Villalobos- Comparan M, Rodriguez-Cruz M, et al. (2008) Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population. Login to comment

[hide] Increase in HDL-C concentration by a dietary portf... Mol Genet Metab. 2010 Oct-Nov;101(2-3):268-72. Epub 2010 Aug 10. Guevara-Cruz M, Tovar AR, Larrieta E, Canizales-Quinteros S, Torres N
Increase in HDL-C concentration by a dietary portfolio with soy protein and soluble fiber is associated with the presence of the ABCA1R230C variant in hyperlipidemic Mexican subjects.
Mol Genet Metab. 2010 Oct-Nov;101(2-3):268-72. Epub 2010 Aug 10., [PMID:20797885]

Abstract [show]
BACKGROUND: A dietary portfolio has been used to reduce blood lipids in hyperlipidemic subjects. To increase the effectiveness of these dietary treatments in specific populations, it is important to study the genetic variability associated with the development of certain types of hyperlipidemias. Low plasma high-density lipoprotein cholesterol (HDL-C) levels are the most common dyslipidemia in Mexican adults and are coupled with the presence of the ABCA1 R230C genotype. Therefore, the aim of this study was to assess the response of HDL-C concentration to a dietary portfolio in a group of Mexican hyperlipidemic subjects with ABCA1R230C (rs9282541) and R219K (rs2230806) polymorphisms. METHODS: Forty-three hyperlipidemic subjects (20 men and 23 women) were given a low saturated fat (LSF) diet for one month, followed by a LSF diet that included 25g of soy protein and 15g of soluble fiber daily for 2months. We analyzed two ABCA1 polymorphisms and studied their association with serum lipids before and after treatment. RESULTS: Hyperlipidemic subjects with the ABCA1 R230C genotype showed lower HDL-C concentrations at the beginning of the study and were better responders to the dietary treatment than subjects with the ABCA1 R230R genotype (+4.6% vs. +14.6%) (p=.05). According to gender and the presence of the R230C genotype, women responded more significantly to the dietary treatment, reflected by an increase of 21.9% in HDL concentration (p=.022), than women with R230R genotype who only experienced an increase of 2.7% in HDL-C concentration. There was no association between the presence of the ABCA1 R219K variant (p=.544) and HDL concentration. CONCLUSION: Hyperlipidemic Mexican subjects with the ABCA1 R230C genotype showed lower HDL-concentrations and were better responders to dietary portfolio treatments for increasing HDL-C concentrations than subjects with the R230R genotype.

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2 Low plasma high-density lipoprotein cholesterol (HDL-C) levels are the most common dyslipidemia in Mexican adults and are coupled with the presence of the ABCA1 R230C genotype. Login to comment
6 Results: Hyperlipidemic subjects with the ABCA1 R230C genotype showed lower HDL-C concentrations at the beginning of the study and were better responders to the dietary treatment than subjects with the ABCA1 R230R genotype (+4.6% vs. +14.6%) (p=.05). Login to comment
7 According to gender and the presence of the R230C genotype, women responded more significantly to the dietary treatment, reflected by an increase of 21.9% in HDL concentration (p=.022), than women with R230R genotype who only experienced an increase of 2.7% in HDL-C concentration. Login to comment
9 Conclusion: Hyperlipidemic Mexican subjects with the ABCA1 R230C genotype showed lower HDL- concentrations and were better responders to dietary portfolio treatments for increasing HDL-C concentrations than subjects with the R230R genotype. Login to comment
18 A frequent cholesterol transporter ABCA1 gene variant (R230C) apparently exclusive to Native American individuals was associated with low HDL-C levels [2], obesity and type 2 diabetes in Mexican Mestizos. Login to comment
32 The high frequency of the ABCA1 R230C variant in the Mexican population has been suggested as a selective advantage. Login to comment
33 Thus, those individuals with the R230C variant probably had a selective advantage during periods of famine. Login to comment
34 However, R230C carriers currently exposed to an obesogenic environment may be prone to the development of diseases grouped under the metabolic syndrome. Login to comment
35 The thrifty genotype may predispose our population to respond in a different way to changes in lifestyle, including changes in diet, which would imply the need to establish strategies to treat dyslipidemias in subjects who are carriers of R230C variant compared with individuals homozygous for the wild type variant R230R. Login to comment
36 Therefore, the aim of this study was to assess the response of HDL-cholesterol concentration to a dietary portfolio consisting of soy protein and soluble fiber in a group of Mexican hyperlipidemic subjects with or without ABCA1(R230C, rs9282541) and R219K (rs2230806) polymorphisms and to evaluate its association with the dietary portfolio in responders and non-responders. Login to comment
62 [22] These two single-nucleotide polymorphisms (SNPs) of the gene ABCA1 (R230C variant (rs9282541) and R219K (rs2230806)) were determined using polymerase chain reaction (PCR)-based TaqMan allele discrimination assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems, Foster City, CA) [26]. Login to comment
70 Results Genotype distribution (wild type allele homozygote, variant heterozygote, variant homozygote) for each polymorphism was as follows: R230C (31, 12, 0) and R219K (19, 21, 3). Login to comment
71 Allele frequencies (wild-type, variant) were for R230C (75.5%, 24.4%) and R219K (68.6%, 31.4%). Login to comment
73 ABCA1 R230C Hyperlipidemic subjects with the ABCA1 R230C variant produced an HDL-C percentage change between basal and final concentration significantly higher after the consumption of the dietary treatment (p=.05) than subjects with the R230R genotype, Table 1. Login to comment
74 Interestingly, subjects with the R230C genotype showed lower basal HDL-C concentrations (36.8±1.3) than subjects with the R230 R (39.9±1.5) genotype. Login to comment
75 Hyperlipidemic subjects with the ABCA1 R230C genotype were better responders to the low saturated fat diet with respect to HDL-C (5% increase) than the wild type genotype subjects (0.65% increase). Login to comment
78 The percent change in HDL-C concentration in the wild type genotype after the dietary treatment was +4.6±2.3%, whereas in subjects with the R230C genotype was +14.6% (p=.05) (Fig. 1). Login to comment
79 According to gender and the presence of the R230C genotype, women responded more significantly to the dietary treatment, reflected by an increase of 21.9% in HDL concentration (p=.022), than women with the R230R genotype who only experienced an increase of 2.7% in HDL-C concentration (Fig. 2). Login to comment
87 The ABCA1 R230C variant is apparently exclusive to Native American individuals and is associated with low HDL-C concentrations [2], obesity [24] and type 2 diabetes in Mexican Mestizos [25]. Login to comment
88 In view of the high frequency of this variant (12%) in Native American populations [2], hyperlipidemic subjects in this study were evaluated with respect to the presence of the ABCA1 R230C variant. Login to comment
89 Interestingly, hyper-responders to the low saturated fat diet and the dietary portfolio with respect to HDL concentrations were subjects who Table 1 Serum lipids in hyperlipidemic subjects after 1 month with LSF diet and after 1 or 2 months of LSF diet and 25 g of soy protein and 15 g of soluble fiber (SSF) according to the ABCA1 R230C. Login to comment
90 BASAL 1st month LSFD 2nd month LSFD+SSF 3rd month LSF+SSF Percentage of change after 3 months of treatment p Total colesterol (mg/dl) R230R 281.4±8.4a 260.3±8.2 b 226.5±6.4 c 222.0±6.2 c -20.2±2.0 .69 R230C 287.8±16.9 a 275.1±19.9 a,b 248.5±15.9 a,b 232.5±13.8 b -18.7±2.8 Triglycerides (mg/dl) R230R 303.6±16.4 a 284.7±21.9 a 159.5±10.8 b 171.0±10.9 b -39.61;4.3 .41 R230C 288.5±23.4 a 298.3±33.2 a 187.6±21.7 b 198.0±27.1 b -32.8±6.9 HDL Cholesterol (mg/dl) R230R 39.9±1.5 39.9±11.4 40.8±1.4 41.3±1.4 +4.6±2.3 .05 R230C 36.8±1.3 38.8±1.9 39.2±1.9 42.1±2.6 +14.6±5.6 LDL Cholesterol (mg/dl) R230R 180.7±9.6 a 163.4±10.4 a,b 153.7±7.4 b 146.4±7.9 b -17.5±3.3 .46 R230C 193.2±16.9 176.7±21.1 171.7±18.0 150.7±16.2 -22.1±5.3 Values are mean±SEM. Differences between the basal and final parameters were evaluated by one-way ANOVA and differences between genotypes and percentage change after treatment were tested with an independent sample Student's t-test. Login to comment
94 Change from baseline in plasma HDL-cholesterol concentration in 43 hyperlipidemic participants divided according to ABCA-1 R230R or R230C genotypes who underwent 1 month of low saturated fat dietary (LSF) treatment, followed by 2 months of LSF with the addition of 25 g of soy protein and 15 g of soluble fiber. Login to comment
96 The p=0.05 value indicates the difference between percentage of change in HDL-C concentration after 3 months of dietary treatment in subjects with R230C genotype. Login to comment
98 Change from baseline in plasma HDL-cholesterol concentration in 23 hyperlipidemic women divided according to ABCA-1 R230R or R230C genotypes who underwent one month of low saturated fat dietary (LSF) treatment, followed by 2 months of LSF with the addition of 25 g of soy protein and 15 g of soluble fiber. Login to comment
99 The p=0.02 value indicates the difference between percentage of change in HDL-C concentration after 3 month of dietary treatment in subjects with R230C genotype. Login to comment
100 presented the ABCA1 R230C genotype. Login to comment
101 As can be seen in Fig. 1, subjects with the ABCA1 R230C genotype showed lower HDL- concentrations at the beginning of the study and were better responders to dietary treatments than subjects with the R230R genotype. Login to comment
102 It has been reported that pharmacological treatment with fenofibrate increased HDL-C by 10% in 228 hyperlipidemic subjects [26], whereas dietary treatment with this specific dietary portfolio increased HDL-C concentration by 14.6% in the 43 patients with hyperlipidemia and 22% in women with the R230C genotype. Login to comment
104 The possible mechanism by which soy protein increases HDL-C concentration in R230C carriers is not clear. Login to comment
112 In Mexico, approximately 3.7 million adults with low HDL-C concentrations and the ABCA1 R230C variant can benefit from the consumption of a specific dietary portfolio. Login to comment

[hide] Association of R230C ABCA1 gene variant with low H... Clin Chim Acta. 2010 Sep 6;411(17-18):1214-7. Epub 2010 Apr 26. Flores-Dorantes T, Arellano-Campos O, Posadas-Sanchez R, Villarreal-Molina T, Medina-Urrutia A, Romero-Hidalgo S, Yescas-Gomez P, Perez-Mendez O, Jorge-Galarza E, Tusie-Luna T, Villalobos-Comparan M, Jacobo-Albavera L, Villamil-Ramirez H, Lopez-Contreras BE, Aguilar-Salinas CA, Posadas-Romero C, Canizales-Quinteros S
Association of R230C ABCA1 gene variant with low HDL-C levels and abnormal HDL subclass distribution in Mexican school-aged children.
Clin Chim Acta. 2010 Sep 6;411(17-18):1214-7. Epub 2010 Apr 26., [PMID:20427018]

Abstract [show]
BACKGROUND: The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults. METHODS: We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. HDL subclass distribution was analyzed in a subgroup of 81 age, gender and BMI-matched children. RESULTS: Individuals carrying the C230 allele showed a significantly lower HDL-C levels (P=2.9x10(-8)), and higher TC/HDL-C ratio, BMI, BMI z-score and percent fat mass (P=0.001, 0.049, 0.032 and 0.039, respectively). HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (P<0.05). Moreover, the proportion of HDL(2b) was lower, while the proportion of HDL(3a) and HDL(3b) particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (P<0.05). CONCLUSIONS: Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children.

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0 Association of R230C ABCA1 gene variant with low HDL-C levels and abnormal HDL subclass distribution in Mexican school-aged children Teresa Flores-Dorantes a , Olimpia Arellano-Campos b , Rosalinda Posadas-Sánchez c , Teresa Villarreal-Molina a , Aida Medina-Urrutia c , Sandra Romero-Hidalgo d , Petra Yescas-Gómez e , Oscar Pérez-Méndez f , Esteban Jorge-Galarza c , Teresa Tusié-Luna a , Marisela Villalobos-Comparán a , Leonor Jacobo-Albavera a , Hugo Villamil-Ramírez a , Blanca E. López-Contreras a , Carlos A. Aguilar-Salinas b , Carlos Posadas-Romero c , Samuel Canizales-Quinteros a, ⁎ a Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico b Department of Endocrinology and Metabolism, INCMNSZ, Mexico City, Mexico c Department of Endocrinology, Instituto Nacional de Cardiología Ignacio Chávez (INCICh), Mexico City, Mexico d Department of Computational Genomics, Instituto Nacional de Medicina Genómica, Mexico City, Mexico e Deparment of Neurogenetics, Instituto Nacional de Neurología, Mexico City, Mexico f Department of Molecular Biology, INCICh, Mexico City, Mexico a b s t r a c ta r t i c l e i n f o Article history: Received 26 October 2009 Received in revised form 20 April 2010 Accepted 21 April 2010 Available online 26 April 2010 Keywords: ABCA1 R230C variant HDL-cholesterol HDL subclasses Mexican children Background: The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. Login to comment
1 We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults. Login to comment
2 Methods: We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. Login to comment
5 HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (Pb0.05). Login to comment
6 Moreover, the proportion of HDL2b was lower, while the proportion of HDL3a and HDL3b particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (Pb0.05). Login to comment
7 Conclusions: Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children. Login to comment
19 We recently found a frequent non-synonymous ABCA1 variant (R230C, rs9282541) exclusive to populations with Native American ancestry, associated with low HDL-C levels, and Clinica Chimica Acta 411 (2010) 1214-1217 ⁎ Corresponding author. Login to comment
25 We thus analyzed the possible effect of the R230C ABCA1 gene variant on HDL-C levels, HDL subclasses and other metabolic traits in healthy Mexican school-aged children. Login to comment
48 HDL subclass distribution analysis HDL subclass distribution was analyzed as described by Medina-Urrutia et al. [26] and compared in different R230C genotypes in a subgroup of 81 school-aged children matched by age, gender and BMI (32 R230R homozygotes, 32 R230C heterozygotes and the 17 available C230C homozygotes). Login to comment
56 R230C genotyping The R230C variant (rs9282541) was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems, Foster City, CA). Login to comment
62 Differences in anthropometric and biochemical parameters according to R230C genotype were analyzed by multiple linear regression analyses, and logistic regression analysis was used to test for association with hypoalphalipoproteinemia, adjusting for age, sex, BMI and Tanner score when appropriate (SPSS ver10.0, Chicago, IL). Login to comment
70 Moreover, C230C and R230C genotypes were significantly more frequent in individuals with hypoalphalipoproteinemia (35 and 24.9%, respectively) than in those with HDL-C levels N35 mg/dl (12.6%, OR 2.19, 95% CI 1.60-2.99, P=9.4×10-7 ). Login to comment
71 Analysis according to gender showed that the effect of R230C on HDL-C levels and hypoalphalipoproteinemia was highly significant in both boys and girls. Login to comment
75 The R230C allele was associated with significantly lower HDL-C levels in pubertal children (45.6±10.9 vs. 41.3±10.9 mg/dl for R230R and R230C/C230C genotypes respectively; P=3.7×10-6 ). Login to comment
76 The same tendency was observed in prepubertal children with marginal significance (48.3±10.6 vs. 45.8±10.4 mg/dl for R230R and R230C/C230C genotypes respectively; P=0.077). Login to comment
77 HDL subclass distribution differed according to R230C genotypes in 81 school-aged children matched by age, gender and BMI (Table 3). Login to comment
79 HDL-C levels were significantly lower in individuals with heterozygous R230C and homozygous C230C genotypes as compared to those with the R230R homozygous genotype (Pb0.05 for both comparisons). Login to comment
80 Moreover, significant differences were observed between the proportion of HDL2b, HDL3a and HDL3b particles and the R230C variant (P=0.002, 0.004 and 0.029, respectively). Login to comment
81 Overall, the proportion of large HDL particles decreased while the proportion of small HDL particles increased in individuals with R230C heterozygous and C230C homozygous genotypes as compared to those with the R230R homozygous genotype (Table 3). Login to comment
82 In addition, the R230C variant was associated with the mean HDL particle size (P=0.014). Login to comment
83 In agreement with the shift toward small HDL particles, mean HDL particle size was significantly smaller in R230C heterozygotes as compared to R230R homozygotes (Pb0.05), and although homozygous C230C subjects showed smaller HDL particles, the difference with R230R homozygotes did not reach statistical significance. Login to comment
93 The only currently identified functional gene variant exclusive and common to Native American populations throughout the Americas is R230C/ABCA1 [35]. Login to comment
94 The association of R230C with low HDL-C levels and hypoalphalipoproteinemia was highly significant while its association with BMI was marginal,inagreementwithpreviousobservationsinMexicanadults[21]. Login to comment
95 However, although a differential effect of some ABCA1 gene polymorphisms according to gender has been previously reported in adults [36], the effect of R230C was independent of gender in Mexican school-aged children. Login to comment
98 R230C was associated with lower HDL-C levels in both pubertal and prepubertal children, although only with marginal significance in the latter group probably because of the reduced sample size. Login to comment
99 Thus, the effect of R230C on HDL-C levels is observed since childhood both in boys and girls. Login to comment
100 R230C affected HDL particle size distribution independently of age, gender and BMI, as the proportion of large HDL particles decreased and the proportion of small HDL particles increased in C230 carriers. Login to comment
104 Although Table 2 Clinical and biochemical parameters according to R230C ABCA1 genotypes in Mexican school-aged children, and stratified by gender. Characteristic R230R R230C C230C Pa Total subjects (%) n=1012 (80.8) n=221 (17.6) n=20 (1.6) Age (years) 11.5±2.4 11.2±2.4 11.6±2.0 NS BMI (kg/m2 ) 21.4±4.4 21.8±4.9 22.5±4.5 0.049 BMI z-score 0.88±0.95 1.02 ± 0.88 1.10±0.98 0.032 FM (%) (n=596) 30.6±10.8 32.1±11.7 35.9±12.9 0.039 TC (mg/dl) 160.5±31.1 157.6±28.1 149.1±36.5 0.019 TG (mg/dl) 114.9±77.6 108.6±52.9 95.1±36.7 NS HDL-C (mg/dl) 46.4±10.9 42.9±11.0 38.2±9.4 2.9×10-8 TC/HDL-C ratio 3.62±1.05 3.87±1.08 4.19±1.12 0.001 HA (%) 12.6 24.9 35.0 9.4×10-7b Boys (%) n=471 (79.2) n=112 (18.8) n=12 (2.0) Age (years) 11.5±2.4 11.2±2.3 11.6±2.3 NS BMI (kg/m2 ) 21.3±4.7 22.1±5.6 21.7±3.8 NS BMI z-score 0.87±1.02 1.05±0.96 1.0±0.98 NS FM (%) (n=287) 29.1±11.9 31.9±13.7 35.2±14.2 0.024 TC (mg/dl) 158.5±30.5 157.9±30.2 150.1±3.8 NS TG (mg/dl) 111.8±85.0 111.5±58.4 92.8±42.2 NS HDL-C (mg/dl) 46.1±11.0 42.8±10.7 38.3±10.9 6.9×10-5 TC/HDL-C ratio 3.61±1.07 3.87±1.09 4.33±1.26 0.007 HA (%) 12.5 22.3 33.3 0.001b Girls (%) n=541 (82.2) n=109 (16.6) n=8 (1.2) Age (years) 11.6±2.4 11.3±2.4 11.7±1.5 NS BMI (kg/m2 ) 21.6±4.4 21.7±4.0 24.5±5.7 NS BMI z-score 0.89±0.88 0.99±0.78 1.30±1.04 NS FM (%) (n=309) 32.0±9.6 32.3±9.4 37.2±11.6 NS TC (mg/dl) 162.2±31.6 157.3±25.9 146.8±25.3 0.020 TG (mg/dl) 117.9±70.7 105.8±47.0 100.5±20.6 NS HDL-C (mg/dl) 46.6±10.8 43.1±11.5 37.8±4.7 1.1×10-4 TC/HDL-C ratio 3.64±1.03 3.87±1.07 3.93±0.816 NS HA (%) 12.6 27.5 37.5 1.8×10-4b Data are the means±SD or n (%). Login to comment
107 Table 3 HDL size and subclass distribution according to R230C ABCA1 genotype groups. Login to comment
108 R230R n=32 R230C n=32 C230C n=17 P-value Age (years) 12.2±1.5 12.2±1.6 11.8±2.0 NS BMI (kg/m²) 23.8±5.5 24.2±6.3 23.0±4.6 NS BMI z-score 1.17±1.01 1.18±0.98 1.15±1.00 NS HDL-C (mg/dl) 48.6±11.0 42.2±11.8 39.4±9.2 0.011a,b HDL2b (%) 13.0±3.6 10.9±2.8 9.8±2.8 0.002a,b HDL2a (%) 21.1±3.5 19.7±3.3 19.9±3.2 NS HDL3a (%) 27.2±1.9 28.3±2.0 29.2±2.1 0.004b HDL3b (%) 23.4±2.6 24.8±2.5 25.0±2.0 0.029 HDL3c (%) 15.2±3.7 16.3±3.8 16.2±4.8 NS HDL size (nm) 8.77±0.17 8.65±0.16 8.64±0.16 0.014a Data are the means±SD or n (%). Login to comment
111 a Pb0.05 after Scheffé post hoc test comparing R230R vs. R230C. Login to comment
115 Although the association of obesity and insulin resistance with smaller HDL particles has been attributed to increased fractional clearance of HDL secondary to depletion of its cholesterol [44,45], in the present study the association of R230C with smaller HDL particles was independent of BMI. Login to comment
118 In conclusion, our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children. Login to comment
72 Analysis according to gender showed that the effect of R230C on HDL-C levels and hypoalphalipoproteinemia was highly significant in both boys and girls. Login to comment
78 The R230C allele was associated with significantly lower HDL-C levels in pubertal children (45.6&#b1;10.9 vs. 41.3&#b1;10.9 mg/dl for R230R and R230C/C230C genotypes respectively; P=3.7&#d7;10-6 ). Login to comment
84 Overall, the proportion of large HDL particles decreased while the proportion of small HDL particles increased in individuals with R230C heterozygous and C230C homozygous genotypes as compared to those with the R230R homozygous genotype (Table 3). Login to comment
85 In addition, the R230C variant was associated with the mean HDL particle size (P=0.014). Login to comment
86 In agreement with the shift toward small HDL particles, mean HDL particle size was significantly smaller in R230C heterozygotes as compared to R230R homozygotes (Pb0.05), and although homozygous C230C subjects showed smaller HDL particles, the difference with R230R homozygotes did not reach statistical significance. Login to comment
96 The only currently identified functional gene variant exclusive and common to Native American populations throughout the Americas is R230C/ABCA1 [35]. Login to comment
97 The association of R230C with low HDL-C levels and hypoalphalipoproteinemia was highly significant while its association with BMI was marginal,inagreementwithpreviousobservationsinMexicanadults[21]. Login to comment
101 R230C was associated with lower HDL-C levels in both pubertal and prepubertal children, although only with marginal significance in the latter group probably because of the reduced sample size. Login to comment
102 Thus, the effect of R230C on HDL-C levels is observed since childhood both in boys and girls. Login to comment
103 R230C affected HDL particle size distribution independently of age, gender and BMI, as the proportion of large HDL particles decreased and the proportion of small HDL particles increased in C230 carriers. Login to comment
110 Table 3 HDL size and subclass distribution according to R230C ABCA1 genotype groups. Login to comment
114 a Pb0.05 after Scheff&#e9; post hoc test comparing R230R vs. R230C. Login to comment
121 In conclusion, our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children. Login to comment

[hide] A functional ABCA1 gene variant is associated with... Hum Mol Genet. 2010 Jul 15;19(14):2877-85. Epub 2010 Apr 23. Acuna-Alonzo V, Flores-Dorantes T, Kruit JK, Villarreal-Molina T, Arellano-Campos O, Hunemeier T, Moreno-Estrada A, Ortiz-Lopez MG, Villamil-Ramirez H, Leon-Mimila P, Villalobos-Comparan M, Jacobo-Albavera L, Ramirez-Jimenez S, Sikora M, Zhang LH, Pape TD, Granados-Silvestre Mde A, Montufar-Robles I, Tito-Alvarez AM, Zurita-Salinas C, Bustos-Arriaga J, Cedillo-Barron L, Gomez-Trejo C, Barquera-Lozano R, Vieira-Filho JP, Granados J, Romero-Hidalgo S, Huertas-Vazquez A, Gonzalez-Martin A, Gorostiza A, Bonatto
A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.
Hum Mol Genet. 2010 Jul 15;19(14):2877-85. Epub 2010 Apr 23., [PMID:20418488]

Abstract [show]
It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

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6 A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. Login to comment
15 We recently found a frequent non-synonymous variant (R230C, rs9282541) within the ATP-binding cassette transporter A1 gene (ABCA1) associated with low high-density lipoprotein cholesterol (HDL-C) levels (the most common dyslipidemia in populations with Native American ancestry), obesity and T2D in Mexican Mestizos (4,5). Login to comment
17 The R230C variant was initially described in the Oji-Cree population (8). Login to comment
20 Because it was previously suggested that R230C may have conferred selective advantage as a thrifty gene and/or resistance against certain infectious diseases (4), we performed a more thorough analysis seeking evidence of positive selection. Login to comment
34 Furthermore, in Native Americans from the Human Genome Diversity Panel (HGDP) (R230C genotypes not available), the ABCA1 5' region ( 75 kb upstream R230C) was clearly enriched for outliers of the integrated haplotype score (iHS) statistic genome-wide distribution (iHS . Login to comment
37 Association of R230C with HDL-C levels and other metabolic traits Overall, the prevalence of hypoalphalipoproteinemia (HA) was the most common dyslipidemia (65% in Mexican and South American natives; Supplementary Material, Table S4). Login to comment
38 Table 1 shows the effect of R230C on HDL-C and total cholesterol levels and body mass index (BMI). Login to comment
39 The R230C/C230C genotypes were significantly associated with low HDL-C levels in Pimas (P ¼ 6.4 × 1025 ) and in the combined analysis of eight Mexican native groups (P ¼ 5.3 × 1028 ). Login to comment
50 The R230C variant occurred on haplogroup B characterized by the ancestral R219 allele, which is frequent in Europe, Asia and America but infrequent in African populations. Login to comment
53 EHH and REHH of ABCA1/R230C and 23 additional SNPs × physical distance in Native American individuals. Login to comment
58 Interestingly, differences in the effect of R230C on lipid profiles were observed in some Native American populations. Login to comment
59 R230C was strongly associated with low total cholesterol and triglyceride levels in Pimas (P ¼ 1.8 × 1027 and P ¼ 7.0 × 1024 , respectively) and Mayans (P ¼ 0.004 and 0.010, respectively). Login to comment
65 Association of R230C with lipid levels and BMI in Native American populations Native American population (n) HDL-C levels Total cholesterol BMI Effect (SE) P-value Effect (SE) P-value Effect (SE) P-value North America USA Pima (2563)a 20.075 (0.019) 6.4 × 1025 20.071 (0.014) 1.8 × 1027 0.008 (0.015) 0.586 Mexico Yaquis (45) - - - - 0.044 (0.018) 0.012 Teenek (67) 20.051 (0.026) 0.057 20.010 (0.024) 0.671 0.001 (0.016) 0.978 Coras (123) 20.033 (0.014) 0.021 20.006 (0.013) 0.681 0.032 (0.011) 0.006 Purepechas (15) 20.040 (0.074) 0.603 20.048 (0.046) 0.333 0.034 (0.019) 0.097 Mazahuas (83) 20.039 (0.036) 0.281 20.031 (0.041) 0.444 0.006 (0.019) 0.758 Nahuas (267) 20.040 (0.014) 0.014 20.014 (0.020) 0.470 20.004 (0.008) 0.617 Totonacas (113) 20.028 (0.021) 0.180 20.031 (0.015) 0.042 0.022 (0.013) 0.085 Zapotecs (106) 20.047 (0.022) 0.038 0.007 (0.019) 0.723 0.007 (0.013) 0.605 Mayans (110) 20.040 (0.017) 0.023 20.043 (0.015) 0.004 20.007 (0.013) 0.554 Mexican natives combined 20.038 (0.007) 5.3 × 1028 20.019 (0.007) 0.027 0.010 (0.004) 0.012 South America Kichwas (79) 20.043 (0.030) 0.153 20.005 (0.020) 0.791 0.024 (0.012) 0.050 Parkateje´ (78) 20.029 (0.026) 0.270 20.002 (0.030) 0.945 0.046 (0.012) 0.0003 All Native Americans combined 20.042 (0.006) 1.77 × 10211 20.021 (0.006) 7.15 × 1025 0.011 (0.003) 0.0001 Effect values are presented as effect size per C230 allele copy, standard error (SE). Login to comment
71 Sequencing and in vitro functional analysis To rule out the presence of another possible causal variant in LD with C230, all 50 exons and the promoter region of ABCA1 were sequenced in a limited number of individuals (2 of each genotype); however, no promoter or coding variant in LD with R230C was found. Login to comment
75 DISCUSSION R230C, a private allele to the Americas The R230C allele first identified in Oji-Crees and Mexican Mestizos was found in most Amerindian groups throughout the Americas, but not in any ethnic group from other continents (4,8). Login to comment
81 It is noteworthy that D9S1120 and R230C (ABCA1) are both located on chromosome 9q, although separated by a 19 Mb distance. Login to comment
87 Evidence suggesting R230C underwent positive selection Understanding the impact of natural selection acting on particular genes in human populations can provide insights into the genetic etiology of human disease. Login to comment
89 The results of the REHH and iHS analyses for the ABCA1 gene region in Native Americans are not compatible with a simple neutral evolutionary model, but are consistent with the hypothesis that the R230C variant resides on a haplotype which is the target of an ongoing directional selective sweep. Login to comment
90 It must be acknowledged, however, that with the currently available genotyping data, it is not possible to define whether the R230C haplotype is also responsible for the signal resulting from the iHS test. Login to comment
92 In the context of Neel`s hypothesis (24), R230C carriers could have had a selective advantage. Login to comment
95 However, under current westernized lifestyle changes, this allele may have become a major susceptibility allele for low HDL-C levels and other metabolic traits, which is consistent with the association of the R230C variant with higher BMI in Native American populations, and with obesity, T2D and metabolic syndrome in Mexican Mestizos (4,5). Login to comment
98 Functional characterization of the ABCA1/R230C variant by lipid efflux assay. Login to comment
99 (A) Polyclonal stable cell lines expressing the ABCA1 wild-type (WT), variant R230C and mutant M1091T (known defective in lipid efflux) were generated, and efflux activity for cholesterol was performed as described in Materials and Methods. Login to comment
103 (B) The expression of WT, variant R230C and mutant M1091T ABCA1 protein in Flp-In cells was assessed by western immunoblotting. Login to comment
108 Association of R230C with HDL-C levels and other metabolic traits Overall, the prevalence of low HDL-C levels was not only higher in Native Americans than in European, Asian and African individuals (3), but also the most common dyslipidemia (65% in Mexican and South American natives). Login to comment
110 R230C/C230C genotypes were strongly associated with low HDL-C levels in Native American rural populations, Pimas and urban Mexican Mestizos (4,9). Login to comment
112 This is consistent with both in silico (PANTHER subPSEC score 24.27) and in vitro evidence confirming that the R230C variant is functional (27% decrease in cholesterol efflux) (22). Login to comment
117 Moreover, a gender effect was observed, as the association of R230C with higher BMI was more significant in males. Login to comment
119 Further studies are required to confirm the role of R230C in these metabolic and other fat storage-related traits such as non-alcoholic fatty liver disease, which is highly prevalent in Hispanic populations (34,35). Login to comment
122 Interestingly, the R230C was only marginally associated with T2D in Pimas (P ¼ 0.06) despite the large sample size and the previous finding that HDL-C concentrations in non-diabetic Pima Indian women were negatively associated with the development of T2D (36). Login to comment
124 The highly significant association of R230C with reduced total cholesterol and triglyceride serum levels observed in Pimas may be one of the factors explaining this marginal association. Login to comment
125 The role of R230C as a risk allele for T2D in Mexican native groups and its interaction with environmental factors requires further analysis. Login to comment
127 We present several lines of evidence in favor of positive selection for the R230C allele possibly contributing to the adaptive evolution of Native American populations and providing insight into the genetic etiology of currently prevalent metabolic disease. Login to comment
140 The 50 exons and proximal promoter region of the 2882 ABCA1 gene were amplified in samples from six individuals (two R230R, two R230C and two C230C) as described previously (8). Login to comment
142 SNP genotyping The R230C variant and 23 SNPs spanning an 800 kb region were genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems). Login to comment
147 Generation of R230C variant constructs and cell lines Polyclonal stable cell lines expressing the ABCA1 R230C variant were generated using the Flp-In system (Invitrogen, Carlsbad, CA, USA) as described previously (42). Login to comment
149 Briefly, the R230C variant was generated by PCR-based site-directed mutagenesis using the primers 230F,5' -GAGCGAGTACTT TGTTCCAACATG and 230R,5' -CATGTTGGAACAAAGT ACTCGCTC and cloned into pcDNA5/FRT (Invitrogen). Login to comment
151 The M1091T ABCA1 mutation previously identified in Tangier patients was used as control (32). Login to comment
169 The LRH test was applied to examine the decay of LD (Sweep software) (48) within an 800 kb region flanking R230C using data obtained from the 20 Native American trios described earlier. Login to comment
177 Associations of R230C genotypes with HDL-C and other metabolic traits were tested using linear regression models (assuming an additive model) adjusting for covariates including age, sex and BMI (SPSS, version 15.0, statistical package; Chicago, IL, USA). Login to comment
9 A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. Login to comment
18 We recently found a frequent non-synonymous variant (R230C, rs9282541) within the ATP-binding cassette transporter A1 gene (ABCA1) associated with low high-density lipoprotein cholesterol (HDL-C) levels (the most common dyslipidemia in populations with Native American ancestry), obesity and T2D in Mexican Mestizos (4,5). Login to comment
23 Because it was previously suggested that R230C may have conferred selective advantage as a thrifty gene and/or resistance against certain infectious diseases (4), we performed a more thorough analysis seeking evidence of positive selection. Login to comment
40 Association of R230C with HDL-C levels and other metabolic traits Overall, the prevalence of hypoalphalipoproteinemia (HA) was the most common dyslipidemia (65% in Mexican and South American natives; Supplementary Material, Table S4). Login to comment
41 Table 1 shows the effect of R230C on HDL-C and total cholesterol levels and body mass index (BMI). Login to comment
42 The R230C/C230C genotypes were significantly associated with low HDL-C levels in Pimas (P &#bc; 6.4 &#d7; 1025 ) and in the combined analysis of eight Mexican native groups (P &#bc; 5.3 &#d7; 1028 ). Login to comment
56 EHH and REHH of ABCA1/R230C and 23 additional SNPs &#d7; physical distance in Native American individuals. Login to comment
61 Interestingly, differences in the effect of R230C on lipid profiles were observed in some Native American populations. Login to comment
62 R230C was strongly associated with low total cholesterol and triglyceride levels in Pimas (P &#bc; 1.8 &#d7; 1027 and P &#bc; 7.0 &#d7; 1024 , respectively) and Mayans (P &#bc; 0.004 and 0.010, respectively). Login to comment
68 Association of R230C with lipid levels and BMI in Native American populations Native American population (n) HDL-C levels Total cholesterol BMI Effect (SE) P-value Effect (SE) P-value Effect (SE) P-value North America USA Pima (2563)a 20.075 (0.019) 6.4 &#d7; 1025 20.071 (0.014) 1.8 &#d7; 1027 0.008 (0.015) 0.586 Mexico Yaquis (45) - - - - 0.044 (0.018) 0.012 Teenek (67) 20.051 (0.026) 0.057 20.010 (0.024) 0.671 0.001 (0.016) 0.978 Coras (123) 20.033 (0.014) 0.021 20.006 (0.013) 0.681 0.032 (0.011) 0.006 Purepechas (15) 20.040 (0.074) 0.603 20.048 (0.046) 0.333 0.034 (0.019) 0.097 Mazahuas (83) 20.039 (0.036) 0.281 20.031 (0.041) 0.444 0.006 (0.019) 0.758 Nahuas (267) 20.040 (0.014) 0.014 20.014 (0.020) 0.470 20.004 (0.008) 0.617 Totonacas (113) 20.028 (0.021) 0.180 20.031 (0.015) 0.042 0.022 (0.013) 0.085 Zapotecs (106) 20.047 (0.022) 0.038 0.007 (0.019) 0.723 0.007 (0.013) 0.605 Mayans (110) 20.040 (0.017) 0.023 20.043 (0.015) 0.004 20.007 (0.013) 0.554 Mexican natives combined 20.038 (0.007) 5.3 &#d7; 1028 20.019 (0.007) 0.027 0.010 (0.004) 0.012 South America Kichwas (79) 20.043 (0.030) 0.153 20.005 (0.020) 0.791 0.024 (0.012) 0.050 Parkateje &#b4; (78) 20.029 (0.026) 0.270 20.002 (0.030) 0.945 0.046 (0.012) 0.0003 All Native Americans combined 20.042 (0.006) 1.77 &#d7; 10211 20.021 (0.006) 7.15 &#d7; 1025 0.011 (0.003) 0.0001 Effect values are presented as effect size per C230 allele copy, standard error (SE). Login to comment
73 Sequencing and in vitro functional analysis To rule out the presence of another possible causal variant in LD with C230, all 50 exons and the promoter region of ABCA1 were sequenced in a limited number of individuals (2 of each genotype); however, no promoter or coding variant in LD with R230C was found. Login to comment
77 DISCUSSION R230C, a private allele to the Americas The R230C allele first identified in Oji-Crees and Mexican Mestizos was found in most Amerindian groups throughout the Americas, but not in any ethnic group from other continents (4,8). Login to comment
83 It is noteworthy that D9S1120 and R230C (ABCA1) are both located on chromosome 9q, although separated by a 19 Mb distance. Login to comment
91 The results of the REHH and iHS analyses for the ABCA1 gene region in Native Americans are not compatible with a simple neutral evolutionary model, but are consistent with the hypothesis that the R230C variant resides on a haplotype which is the target of an ongoing directional selective sweep. Login to comment
94 In the context of Neel`s hypothesis (24), R230C carriers could have had a selective advantage. Login to comment
97 However, under current westernized lifestyle changes, this allele may have become a major susceptibility allele for low HDL-C levels and other metabolic traits, which is consistent with the association of the R230C variant with higher BMI in Native American populations, and with obesity, T2D and metabolic syndrome in Mexican Mestizos (4,5). Login to comment
100 Functional characterization of the ABCA1/R230C variant by lipid efflux assay. Login to comment
101 (A) Polyclonal stable cell lines expressing the ABCA1 wild-type (WT), variant R230C and mutant M1091T (known defective in lipid efflux) were generated, and efflux activity for cholesterol was performed as described in Materials and Methods. Login to comment
105 (B) The expression of WT, variant R230C and mutant M1091T ABCA1 protein in Flp-In cells was assessed by western immunoblotting. Login to comment
114 This is consistent with both in silico (PANTHER subPSEC score 24.27) and in vitro evidence confirming that the R230C variant is functional (27% decrease in cholesterol efflux) (22). Login to comment
121 Further studies are required to confirm the role of R230C in these metabolic and other fat storage-related traits such as non-alcoholic fatty liver disease, which is highly prevalent in Hispanic populations (34,35). Login to comment
126 The highly significant association of R230C with reduced total cholesterol and triglyceride serum levels observed in Pimas may be one of the factors explaining this marginal association. Login to comment
129 We present several lines of evidence in favor of positive selection for the R230C allele possibly contributing to the adaptive evolution of Native American populations and providing insight into the genetic etiology of currently prevalent metabolic disease. Login to comment
144 SNP genotyping The R230C variant and 23 SNPs spanning an 800 kb region were genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems). Login to comment
171 The LRH test was applied to examine the decay of LD (Sweep software) (48) within an 800 kb region flanking R230C using data obtained from the 20 Native American trios described earlier. Login to comment
179 Associations of R230C genotypes with HDL-C and other metabolic traits were tested using linear regression models (assuming an additive model) adjusting for covariates including age, sex and BMI (SPSS, version 15.0, statistical package; Chicago, IL, USA). Login to comment

[hide] HDL and LDL cholesterol significantly influence be... Curr Opin Lipidol. 2010 Jun;21(3):178-85. Kruit JK, Brunham LR, Verchere CB, Hayden MR
HDL and LDL cholesterol significantly influence beta-cell function in type 2 diabetes mellitus.
Curr Opin Lipidol. 2010 Jun;21(3):178-85., [PMID:20463468]

Abstract [show]
PURPOSE OF REVIEW: Patients with type 2 diabetes mellitus (T2DM) display significant abnormalities in both LDL and HDL particles. Recent data suggest that these changes in lipoprotein particles could contribute to the pathogenesis of T2DM. In this review, we focus on these abnormalities and discuss their possible impact on beta-cell function and beta-cell mass. RECENT FINDINGS: Infusion of reconstituted HDL in T2DM patients improves beta-cell function, whereas carriers of loss-of-function mutations in the cholesterol transporter ABCA1, who have decreased HDL levels, have impaired beta-cell function. In addition, recent studies show that HDL protects against stress-induced beta-cell apoptosis in vitro. Finally, increasing evidence points to a role for islet inflammation in the pathogenesis of T2DM. ABCA1 and ABCG1 may also modulate these inflammatory responses, suggesting an additional pathway by which HDL may impact T2DM. SUMMARY: Recent findings indicate that HDL protects beta-cells from cholesterol-induced beta-cell dysfunction, stress-induced apoptosis and islet inflammation. As the protective properties of HDL are compromised in patients with metabolic syndrome and T2DM, dysfunctional HDL metabolism could contribute to the pathogenesis of T2DM. Therapeutic normalization of both the quantity and quality of HDL particles may be a novel approach to prevent or treat T2DM.

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45 Initial evidence suggesting that changes in ABCA1 activity could influence glucose homeostasis in humans came from a study of the R230C polymorphism in ABCA1 in the Mexican population. Login to comment
47 Functional analysis shows a 30% decrease in cholesterol efflux compared to wild-type ABCA1, indicating that the R230C is indeed a partial loss-of-function mutation (S. Canizales-Quinteros, unpublished data). Login to comment

[hide] Carriers of loss-of-function mutations in ABCA1 di... Diabetes Care. 2010 Apr;33(4):869-74. Epub 2010 Jan 12. Vergeer M, Brunham LR, Koetsveld J, Kruit JK, Verchere CB, Kastelein JJ, Hayden MR, Stroes ES
Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction.
Diabetes Care. 2010 Apr;33(4):869-74. Epub 2010 Jan 12., [PMID:20067955]

Abstract [show]
OBJECTIVE: Abnormal cellular cholesterol handling in islets may contribute to beta-cell dysfunction in type 2 diabetes. beta-Cell deficiency for the ATP binding cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol, leads to altered intracellular cholesterol homeostasis and impaired insulin secretion in mice. We aimed to assess the impact of ABCA1 dysfunction on glucose homeostasis in humans. RESEARCH DESIGN AND METHODS: In heterozygous carriers of disruptive mutations in ABCA1 and family-based noncarriers of similar age, sex, and BMI, we performed oral glucose tolerance tests (OGTTs) (n = 15 vs. 14) and hyperglycemic clamps (n = 8 vs. 8). RESULTS: HDL cholesterol levels in carriers were less than half those in noncarriers, but LDL cholesterol levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after an OGTT were mildly higher in carriers than in noncarriers. During hyperglycemic clamps, carriers demonstrated lower first-phase insulin secretion than noncarriers but no difference in insulin sensitivity. The disposition index (a measure of beta-cell function adjusted for insulin sensitivity) of the carriers was significantly reduced in ABCA1 heterozygotes. CONCLUSIONS: Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance. Our data provide evidence that ABCA1 is important for normal beta-cell function in humans.

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16 In addition, the common ABCA1 polymorphism R230C was shown to be associated with a fourfold increase in the occurrence of diabetes in a Mexican population (6). Login to comment
17 In addition, the common ABCA1 polymorphism R230C was shown to be associated with a fourfold increase in the occurrence of diabetes in a Mexican population (6). Login to comment

[hide] Cholesterol in beta-cell dysfunction: the emerging... Curr Diab Rep. 2010 Feb;10(1):55-60. Brunham LR, Kruit JK, Hayden MR, Verchere CB
Cholesterol in beta-cell dysfunction: the emerging connection between HDL cholesterol and type 2 diabetes.
Curr Diab Rep. 2010 Feb;10(1):55-60., [PMID:20425068]

Abstract [show]
Beta-cell dysfunction is a critical step in the pathogenesis of type 2 diabetes. The mechanisms responsible for beta-cell death and dysfunction remain incompletely understood, but include glucolipotoxicity, the deleterious metabolic milieu created by high plasma concentrations of glucose and lipid species. Recently, an important role has emerged for cholesterol in this process. In this article, we review recent advances in our understanding of the role of ABCA1 and cholesterol metabolism in beta-cell function, with particular attention to insights gained from human studies.

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20 Initial studies assessed the association of a presumed loss-of-function polymorphism in the ABCA1 gene, R230C, with metabolic parameters in a Mexican population [11]. Login to comment
25 An important question has been whether the R230C variant is itself functional, or whether its association with metabolic parameters and diabetes represents linkage with another, functional variant in close proximity. Login to comment
26 We studied the functional effects of the R230C variant in stable cell lines and found that it elicits approximately 30% less cholesterol efflux than wild-type ABCA1, indicating that this is a loss-of-function mutation, and explaining the deleterious phenotype observed in carriers of this variant (Samuel Canizales-Quinteros, Personal communication). Login to comment

[hide] The cell cholesterol exporter ABCA1 as a protector... Biochim Biophys Acta. 2009 Jul;1791(7):563-72. Epub 2009 Apr 1. Tang C, Oram JF
The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes.
Biochim Biophys Acta. 2009 Jul;1791(7):563-72. Epub 2009 Apr 1., [PMID:19344785]

Abstract [show]
ATP-binding cassette transporter A1 (ABCA1) is an integral cell membrane protein that exports cholesterol from cells and suppresses macrophage inflammation. ABCA1 exports cholesterol by a multistep pathway that involves forming cell-surface lipid domains, solubilizing these lipids by apolipoproteins, binding of apolipoproteins to ABCA1, and activating signaling processes. Thus, ABCA1 behaves both as a lipid exporter and a signaling receptor. ABCA1 transcription is highly induced by sterols, and its expression and activity are regulated post-transcriptionally by diverse processes. ABCA1 mutations can reduce plasma HDL levels, accelerate cardiovascular disease, and increase the risk for type 2 diabetes. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels, inflammation, atherogenesis, and pancreatic beta cell function. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages, raising the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become a promising new therapeutic target for treating cardiovascular disease and diabetes.

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217 In particular, subjects with the R230C polymorphism in the Mexican population have low HDL, increased body mass, elevated hemoglobin A1c levels, reduced fasting insulin, and early onset type 2 diabetes [125-128]. Login to comment
216 In particular, subjects with the R230C polymorphism in the Mexican population have low HDL, increased body mass, elevated hemoglobin A1c levels, reduced fasting insulin, and early onset type 2 diabetes [125-128]. Login to comment

[hide] Association of the ATP-binding cassette transporte... Diabetes. 2008 Feb;57(2):509-13. Epub 2007 Nov 14. Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, Huertas-Vazquez A, Menjivar M, Romero-Hidalgo S, Wacher NH, Tusie-Luna MT, Cruz M, Aguilar-Salinas CA, Canizales-Quinteros S
Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population.
Diabetes. 2008 Feb;57(2):509-13. Epub 2007 Nov 14., [PMID:18003760]

Abstract [show]
OBJECTIVE: The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic beta-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS: The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20-69 years (121 with onset </=45 years), and 202 nondiabetic control subjects aged >50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS: R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis </=45 years) (OR 3.776, P = 3.3 x 10(-6)). Both associations remained significant after adjusting for admixture (P = 0.0008 and P = 8.1 x 10(-6), respectively). Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P = 7.6 x 10(-6) and 9.4 x 10(-8), respectively). CONCLUSIONS: The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population.

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0 Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population M. Teresa Villarreal-Molina,1 M. Teresa Flores-Dorantes,1 Olimpia Arellano-Campos,2 Marisela Villalobos-Comparan,1 Maricela Rodrı´guez-Cruz,3 Angel Miliar-Garcı´a,4 Adriana Huertas-Vazquez,1 Marta Menjivar,5 Sandra Romero-Hidalgo,6 Niels H. Wacher,7 M. Teresa Tusie-Luna,1 Miguel Cruz,7 Carlos A. Aguilar-Salinas,2 Samuel Canizales-Quinteros,1 and the Metabolic Study Group OBJECTIVE-The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Login to comment
4 RESULTS-R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P ϭ 0.001). Login to comment
7 Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P ϭ 7.6 ϫ 10-6 and 9.4 ϫ 10-8 , respectively). Login to comment
8 CONCLUSIONS-The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population. Login to comment
18 Based on this evidence, we sought to confirm and further investigate the role of the ABCA1 R230C variant in type 2 diabetes in this population. Login to comment
46 R230C and four additional single nucleotide polymorphisms (SNPs) (rs3818689, rs2487037, rs2000069 and rs2230806) contained in three haplotype blocks within the ABCA1 gene were genotyped using Taqman assays (ABI Prism 7900HT Sequence Detection System, Applied Biosystems). Login to comment
52 Although associations were tested under dominant, recessive, or additive models, because the number of C230C homozygotes was reduced, the dominant model (R230C/C230C vs. R230R) was considered the most appropriate. Login to comment
59 Significantly lower fasting insulin and higher A1C levels were observed in R230C/C230C than in R230R diabetic subjects (P ϭ 0.011 and 0.015, respectively; adjusted by age, sex, BMI, duration of diabetes, and treatment); however, differences in insulin levels according to genotype were not observed in nondiabetic subjects. Login to comment
60 Overall, R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%, OR 2.501, 95% CI 1.476-4.238, P ϭ 0.001) (Table 2), even after adjusting for admixture (P ϭ 0.0008). Login to comment
61 Interestingly, age at diagnosis was significantly lower in R230C/C230C than in R230R diabetic individuals (42.6 Ϯ 9.3 years vs. 47.0 Ϯ 10.9 years, respectively; P ϭ 0.005, adjusted by sex and BMI) (Table 1). Login to comment
62 We then tested the association of R230C with early-onset type 2 diabetes (Յ45 years, n ϭ 121), based on the average age of diagnosis of R230C/C230C individuals and on the previous use of 45 years as the cutoff age in linkage and association studies for type 2 diabetes (17,18). Login to comment
63 While the association of R230C/C230C with late-onset type 2 diabetes (Ͼ45 years, n ϭ 123) was not significant (P ϭ 0.149), its association with early-onset type 2 diabetes was highly significant (OR 3.776, 95% CI 2.121-6.748, P ϭ 3.3 ϫ 10-6 ) even after adjusting for admixture (8.1 ϫ 10-6 ) (Table 2). Login to comment
64 TABLE 1 Clinical and biochemical parameters of the initial study group Type 2 diabetic patients Type 2 diabetic patients Nondiabetic control subjects R230R R230C/C230C n 244 202 184 60 Males (%) 31.6 30.2 29.9 36.7 Age (years) 53.9 Ϯ 12.6 60.5 Ϯ 9.4* 54.6 Ϯ 12.4 51.7 Ϯ 13.1 Age at diagnosis (years) 45.8 Ϯ 10.7 - 47.0 Ϯ 10.9 42.6 Ϯ 9.3§ BMI (kg/m2 ) 28.4 Ϯ 4.8 27.4 Ϯ 4.3† 28.3 Ϯ 4.8 28.9 Ϯ 4.7 Fasting glucose (mmol/l) 9.8 Ϯ 4.3 4.9 Ϯ 0.6* 9.8 Ϯ 4.3 9.8 Ϯ 4.5 Fasting insulin (pmol/l) 71.1 Ϯ 54.6 51.2 Ϯ 40.6* 75.2 Ϯ 59.0 58.3 Ϯ 35.3‡ A1C (%) (n ϭ 141) 8.9 Ϯ 2.3 ND 8.7 Ϯ 2.2 9.9 Ϯ 2.5‡ HOMA-IR 4.9 Ϯ 5.1 1.9 Ϯ 1.5* 5.5 Ϯ 5.9 4.3 Ϯ 2.9 HOMA-beta 60.9 Ϯ 53.2 140.3 Ϯ 161.9* 62.3 Ϯ 53.9 57.1 Ϯ 51.4 HDL cholesterol (mmol/l) 1.1 Ϯ 0.3 1.3 Ϯ 0.4* 1.1 Ϯ 0.3 1.0 Ϯ 0.3 Apo A-I (mg/dl) 132.7 Ϯ 25.8 147.4 Ϯ 22.9* 134 Ϯ 27.1 125 Ϯ 22.3 Treatment (%) - Not treated 27 (15.3) 18 (13.4) 9 (20.9) Diet plus exercise 8 (4.5) 7 (5.2) 1 (2.3) OHA 124 (70.8) 95 (70.1) 29 (67.4) OHA plus insulin 14 (8.2) 11 (8.2) 3 (6.9) Insulin 4 (2.3) 3 (2.2) 1 (2.3) Data are means Ϯ SD unless otherwise indicated. Login to comment
65 *P Ͻ 0.001, †P Ͻ 0.05 comparing type 2 diabetic patients with nondiabetic subjects; ‡P Ͻ 0.05, R230C/C230C vs. R230R, adjusted for age, sex, BMI, duration of diabetes, and treatment (patients with insulin treatment were excluded); §P Յ 0.005, adjusted for sex and BMI. Login to comment
68 There was no evidence for LD between R230C and the other four SNPs. Login to comment
69 Individually, all SNPs other than R230C failed to show association with type 2 diabetes (P Ͼ 0.311, Table 3). Login to comment
72 The results were very similar, as 24.8% of type 2 diabetic individuals and 13.8% of control subjects had R230C/C230C genotypes (OR 2.098, 95% CI 1.255-3.507, P ϭ 0.005). Login to comment
73 However, although R230C remained significantly associated with early-onset type 2 diabetes (OR 2.190, 95% CI 1.258-3.732, P ϭ 0.004), the improvement in significance was less evident than that observed in the initial study group. Login to comment
74 We were not able to test the association of R230C with fasting insulin levels and A1C in the replication group, as this information was not available. Login to comment
75 R230C/C230C type 2 diabetic individuals had a significantly lower age at diagnosis (44.1 Ϯ 9.2 years vs. 46.56 Ϯ 10.9 years, P ϭ 0.028), and higher BMI (29.1 Ϯ 4.2 vs. 28.3 Ϯ 4.2 kg/m2 , P ϭ 0.047) than in R230R type 2 diabetes subjects in both study populations (data not shown). Login to comment
76 The combined analysis of both groups revealed a highly significant association of R230C with type 2 diabetes (OR 2.097, 95% CI 1.483-2.960, P ϭ 7.6 ϫ 10-6 ), particularly with early-onset type 2 diabetes (OR 2.757, 95% CI 1.869-3.917, P ϭ 9.4 ϫ 10-8 ). Login to comment
78 To test whether the association of the R230C variant with type 2 diabetes is independent of its previously reported association with obesity (12), we tested the association including only obese individuals. Login to comment
79 R230C/ C230C genotypes were significantly more frequent in obese diabetic than in obese nondiabetic individuals (P ϭ 0.001). Login to comment
80 DISCUSSION The ABCA1 R230C variant was significantly associated with type 2 diabetes in the Mexican population. Login to comment
82 Moreover, R230C was not in LD with any other SNP tested in neighboring haplotype blocks within the ABCA1 gene, suggesting that the R230C variant is functional and is a significant risk allele for type 2 diabetes in the Mexican population. Login to comment
84 This is epidemiologically relevant in TABLE 2 R230C genotype frequencies in type 2 diabetic patients and nondiabetic control subjects stratified according to age of onset of type 2 diabetes Genotype ͓n (%)͔ OR P * vs. nondiabeticR230R R230C/C230C Initial study group Type 2 diabetic patients (n ϭ 244) 184 (75.4) 60 (24.6) 2.501 0.001 Early-onset type 2 diabetes (n ϭ 121) 81 (66.9) 40 (33.1) 3.776 3.3 ϫ 10-6 Late-onset type 2 diabetes (n ϭ 123) 103 (83.7) 20 (16.3) 1.619 0.149 Nondiabetic subjects (n ϭ 202) 179 (88.6) 23 (11.4) Replication group Type 2 diabetic patients (n ϭ 242) 182 (75.2) 60 (24.8) 2.098 0.005 Early-onset type 2 diabetes (n ϭ 119) 88 (73.9) 31 (26.1) 2.190 0.004 Late-onset type 2 diabetes (n ϭ 123) 94 (76.4) 29 (23.6) 1.935 0.032 Nondiabetic subjects (n ϭ 225) 194 (86.2) 31 (13.8) Combined analysis Type 2 diabetic patients (n ϭ 486) 366 (75.3) 120 (24.7) 2.097 7.6 ϫ 10-6 Early-onset type 2 diabetes (n ϭ 240) 169 (70.4) 71 (29.6) 2.757 9.4 ϫ 10-8 Late-onset type 2 diabetes (n ϭ 246) 197 (80.1) 49 (19.9) 1.826 0.010 Nondiabetic subjects (n ϭ 427) 373 (87.4) 54 (12.6) Data are n (%). Login to comment
85 *P values and ORs calculated by a logistic regression analysis using a dominant model (R230C/C230C vs. R230R) with adjustment for sex and BMI. Login to comment
87 TABLE 3 Allelic association analyses results of individual SNPs in the ABCA1 gene in case-control samples of the initial study group dbSNP ID Position* ABCA1 region Major/minor allele MAF Allele frequencies P† P‡ Type 2 diabetes Nondiabetic rs2000069 106675690 Intron 5 C/T 0.380 0.372 0.390 0.729 0.999 rs2230806 (R219K) 106660688 Exon 7 G/A 0.327 0.312 0.346 0.311 0.845 rs9282541 (R230C) 106660656 Exon 7 C/T 0.097 0.131 0.056 0.0002 0.001 rs2487037 106657158 Intron 7 C/T 0.261 0.256 0.267 0.585 0.998 rs3818689 106634837 Intron 18 G/C 0.054 0.056 0.052 0.772 0.999 *Position is in contiguous NT_008470.18; †P values for type 2 diabetes with respect to the minor allele; ‡P values after Bonferroni correction for the five different SNPs tested. Login to comment
90 It is important to point out that this study was conducted based on a previous observation in a reduced group of diabetic individuals who showed a very high frequency of R230C/C230C genotypes (41.2%) (12). Login to comment
93 This age difference or other population stratification factors may explain the higher R230C/C230C genotype frequency reported in first group. Login to comment
95 Because R230C was previously found to be associated with obesity and obesity-related comorbidities (12), it could be speculated that it confers susceptibility to type 2 diabetes through obesity and insulin resistance. Login to comment
102 In addition to its effect on insulin secretion, R230C may also be associated with type 2 diabetes through an increased risk of obesity. Login to comment
103 However, the R230C/C230C genotypes were significantly more frequent in obese diabetic than in obese nondiabetic individuals, suggesting that both associations may be independent. Login to comment
105 In conclusion, our findings suggest there is an association of the R230C variant with early-onset type 2 diabetes in Mexican-Mestizos, which is in accordance with recent findings on beta-cell physiology and the effects of cholesterol lipotoxicity on insulin secretion. Login to comment
124 There is no evidence for LD between the R230C variant and the other four SNPs. Login to comment
125 However, SNPs rs2230806 (R219K) and r2487037 were in high LD (r2 >0.8). Login to comment

[hide] The ATP-binding cassette transporter A1 R230C vari... Diabetes. 2007 Jul;56(7):1881-7. Epub 2007 Feb 7. Villarreal-Molina MT, Aguilar-Salinas CA, Rodriguez-Cruz M, Riano D, Villalobos-Comparan M, Coral-Vazquez R, Menjivar M, Yescas-Gomez P, Konigsoerg-Fainstein M, Romero-Hidalgo S, Tusie-Luna MT, Canizales-Quinteros S
The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities.
Diabetes. 2007 Jul;56(7):1881-7. Epub 2007 Feb 7., [PMID:17287470]

Abstract [show]
Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.

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0 Original Article The ATP-Binding Cassette Transporter A1 R230C Variant Affects HDL Cholesterol Levels and BMI in the Mexican Population Association With Obesity and Obesity-Related Comorbidities M. Teresa Villarreal-Molina,1,2 Carlos A. Aguilar-Salinas,3 Maricela Rodrı´guez-Cruz,4 Daniela Rian˜o,3 Marisela Villalobos-Comparan,1 Ramon Coral-Vazquez,5 Marta Menjivar,6 Petra Yescas-Gomez,7 Mina Ko¨nigsoerg-Fainstein,8 Sandra Romero-Hidalgo,9 M. Teresa Tusie-Luna,1 Samuel Canizales-Quinteros,1 and the Metabolic Study Group* Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Login to comment
2 A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P ‫؍‬ 0.00006). Login to comment
4 R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. Login to comment
35 A nonsynonymous sequence change (R230C) previously reported as a rare variant or mutation causing familial hypoalfalipoproteinemia in an Oji-Cree individual (22) was found to be strikingly common in Mexican individuals with low HDL cholesterol levels. Login to comment
36 This led us to screen for the presence of R230C and analyze its effect on HDL cholesterol levels and several other clinical/metabolic traits in the general population of Mexico City. Login to comment
77 R230C variant genotyping. Login to comment
78 The general Mexican-Mestizo and Amerindian populations were screened for the R230C variant by TaqMan assay, and allelic discrimination was performed on an ABI Prism 7900HT sequence detection system (Applied Biosystems). Login to comment
99 R230C genotype frequencies according to HDL levels (low-HDL cholesterol group [Յ10th percentile] and high-HDL cholesterol group [Ն90th percentile]) are given in Table 1. Login to comment
100 R230C/C230C genotypes were significantly more frequent in the low-HDL cholesterol than the high-HDL cholesterol group (45 vs. 2.9%, P ϭ 0.00006, P ϭ 0.0005 after adjusting for admixture). Login to comment
102 The relationship of the R230C variant with anthropometric and biochemical measurements is shown in Table 2. Login to comment
103 Significantly lower HDL cholesterol and apoA-I levels were observed in individuals with R230C/C230C genotypes (44.4 Ϯ 11.1 and 131.9 Ϯ 24.4 mg/dl, respectively) as compared with those with the R230R genotype (48.7 Ϯ 13.8 and 141.1 Ϯ 23.8 mg/dl, P ϭ 0.024 and 0.001, respectively). Login to comment
104 Interestingly, R230C/C230C individuals displayed higher average BMI and waist measurements (29.3 Ϯ 6.4 kg/m2 and 93.1 Ϯ 14.5 cm, respectively) than R230R individuals (27.1 Ϯ 5.3 and 90.1 Ϯ 13.1 cm, P ϭ 0.005 and 0.048, respectively). Login to comment
106 Because both parameters showed association with the R230C variant, we additionally adjusted all other parameters for HDL cholesterol and apoA-I levels. Login to comment
108 Moreover, including only individuals with apoA-I levels Ͼ130 mg/dl (mean apoA-I levels of R230C carriers), the association with higher BMI remained significant (P ϭ 0.018). Login to comment
111 R230C/C230C genotypes were associated with an increased risk of obesity (OR 2.527, 95% CI 1.667-3.819, P ϭ 0.005). Login to comment
113 In addition, HDL and apoA-I serum levels were not significantly different in R230C/C230C obese and non-R230C obese individuals (42.9 Ϯ 10.3 and 134.9 Ϯ 20.3 mg/dl vs. 43.7 Ϯ 8.5 and 135.7 Ϯ 27.2 mg/dl, P ϭ 0.380 and 0.242, respectively). Login to comment
115 The R230C genotype distribution in subjects with and without metabolic syndrome is presented in Table 3, which includes 86 more metabolic syndrome case and control subjects not previously included in the general Mestizo population. Login to comment
116 R230C/C230C genotypes were significantly more frequent in metabolic syndrome than in non-metabolic syndrome subjects according to both ATP-III criteria (OR 1.893, 95% CI 1.483-2.460, P ϭ 0.0007) and IDF criteria (1.775, 1.370-2.336, P ϭ 0.003). Login to comment
117 The association of the R230C variant with the metabolic syndrome remained significant after adjusting for admixture under both criteria (1.833, 1.405-2.425, P ϭ 0.001; and 1.745, 1.328-2.298, P ϭ 0.005, respectively). Login to comment
118 Because the R230C variant was more frequent in diabetic individuals in the overall population, we compared the R230C genotype distribution in type 2 diabetic and non-type 2 diabetic subjects. Login to comment
120 R230C/ C230C genotypes were significantly more frequent in type 2 diabetic than in non-type 2 diabetic individuals (41.2 vs. TABLE 1 R230C genotype and allele frequencies in Mexican individuals with hypo- and hyperalphalipoproteinemia Low HDL cholesterol High HDL P Genotype R230R 22 (55.0) 33 (97.1) 0.00006* R230C 15 (37.5) 1 (2.90) - C230C 3 (7.5) 0 - Allele R230 59 (73.8) 67 (98.5) 0.00002 C230 21 (26.2) 1 (1.5) - Data are n (%). Login to comment
121 *P value comparing R230C/C230C vs. R230R. Login to comment
122 TABLE 2 Clinical and biochemical parameters in R230C carriers and noncarriers in the general population of Mexico City Characteristic R230R R230C/ C230C P* n 343 86 - Males 37.0 31.5 - Age (years) 40.1 Ϯ 12.8 40.2 Ϯ 10.5 0.767 Smoker 26.3 28.4 0.586† Menopause 8.9 7.4 0.717† BMI (kg/m2 ) 27.1 Ϯ 5.3 29.3 Ϯ 6.4 0.005 Waist (cm) 90.1 Ϯ 13.1 93.1 Ϯ 14.5 0.048 Obesity 38.5 64.8 0.003† Diabetes 5.8 16.3 0.003† SBP (mmHg) 119.4 Ϯ 18.9 119.6 Ϯ 15.6 0.924 DBP (mmHg) 79.3 Ϯ 10.4 80.0 Ϯ 11.7 0.738 Fasting glucose (mg/dl) 97.3 Ϯ 33.7 105.0 Ϯ 43.5 0.346 Fasting insulin (␮U/ml) 10.5 Ϯ 7.6 11.6 Ϯ 8.0 0.674 HOMA-IR 2.65 Ϯ 3.3 3.0 Ϯ 2.5 0.712 Cholesterol (mg/dl) 211.0 Ϯ 42.9 207.2 Ϯ 41.1 0.803 Triglycerides (mg/dl) 184.7 Ϯ 140.6 191.2 Ϯ 141.9 0.913 HDL cholesterol (mg/dl) 48.7 Ϯ 13.8 44.4 Ϯ 11.1 0.024 ApoA-I (mg/dl) 141.1 Ϯ 23.8 131.9 Ϯ 24.4 0.001 ApoB (mg/dl) 112.7 Ϯ 28.9 112.9 Ϯ 28.3 0.929 Data are the means Ϯ SE or %. Login to comment
124 *P value comparing R230C/C230C vs. R230R, adjusted for age, sex, BMI, triglyceride levels, smoking, and educational level; †Fisher`s exact two-tailed test. Login to comment
128 Moreover, although BMI was significantly higher in R230C than in non-R230C diabetic individuals (32.3 Ϯ 4.8 vs. 27.8 Ϯ 5.1 kg/m2 , P ϭ 0.048), HDL and apoA-I serum levels showed no significant differences between these groups (P ϭ 0.262 and 0.082, respectively). Login to comment
131 Allele and genotype frequencies of the R230C variant in Mexican-Mestizos and five Mexican Amerindian populations are shown in Table 4. Login to comment
132 R230C genotype frequencies did not significantly deviate from Hardy-Weinberg equilibrium in any group, except in Yaquis, where an excess of C230C homozygotes was found. Login to comment
135 The high frequency of a probably functional ABCA1 variant (R230C) in the Mexican population provides a unique opportunity to assess associations with HDL cholesterol and apoA-I levels, as well as with other clinical/metabolic traits. Login to comment
136 The R230C variant has not been functionally tested, so the marker under study may be in linkage disequilibrium with a causative genomic variant within or proximal to the study locus. Login to comment
138 Other facts strongly suggest that the variant is functional: 1) R230C occurs at the first extracellular loop, where Tangier and familial hypoalfalipoproteinemia mutations are clustered (35); 2) the arginine at position 230 is conserved between species; and 3) the nature of the amino acids involved is very different: whereas arginine is basic, positively charged, and hydrophilic, cysteine is hydrophobic and contains a sulfhydril group. Login to comment
141 The effect of ABCA1 mutations on HDL cholesterol serum concentrations is well known, and R230C exerted a modest but clear HDL cholesterol/apoA-I-decreasing effect. Login to comment
142 We infer that R230C affects cholesterol efflux in HDL-forming cells because it was significantly associated with decreased HDL cholesterol and apoA-I levels, regardless of age, sex, smoking, BMI, triglyceride levels, and educational level. Login to comment
145 Thus, the high frequency of R230C in Mexicans may be responsible for this modest peak. Login to comment
146 R230C does not seem to abolish cholesterol efflux in HDL-forming cells, but it could be a functional variant. Login to comment
148 Because Ͼ50 different genes are involved in regulating HDL cholesterol (37), the presence of TABLE 3 Association of the R230C variant in the ABCA1 gene with obesity and the metabolic syndrome Metabolic trait Genotype OR PR230R R230C/C230C Obese subjects 84 (71.2) 34 (28.8) 2.527 0.005* Nonobese 139 (86.8) 21 (13.2) - - Metabolic syndrome subjects‡ 143 (73.7) 51 (26.3) 1.893 0.0007† Non-metabolic syndrome 268 (84.8) 48 (15.2) - - Data are n (%). Login to comment
151 TABLE 4 R230C genotype and allele frequencies in Amerindian populations of Mexico Group n Genotype Allele P*R230R R230C C230C R230 C230 Yaqui 37 0.703 0.189 0.108 0.797 0.203 0.013 Teenek 67 0.671 0.299 0.030 0.821 0.179 0.015 Mazahua 88 0.818 0.170 0.011 0.903 0.097 NS Purépecha 35 0.629 0.314 0.057 0.786 0.214 0.007 Mayan 40 0.450 0.525 0.025 0.718 0.288 0.00001 Mestizos 429 0.799 0.183 0.018 0.891 0.109 - *P value when compared with allelic frequencies of the Mestizos. Login to comment
152 functional variants in others genes (such as cholesterol ester transfer protein or hepatic lipase) could increase HDL cholesterol levels, and this may explain why one R230C heterozygote was found in the high-HDL cholesterol group (15). Login to comment
156 The association of R230C with BMI in Mexican Mestizos was more significant than that observed for lowering HDL cholesterol levels. Login to comment
159 In addition, when individuals with apoA-I levels Ͻ130 mg/dl (mean apoA-I levels of R230C carriers) were excluded from the analysis, the association remained significant, strongly suggesting that the role of ABCA1 in the pathophysiology of obesity is independent of its role in regulating HDL cholesterol and apoA-I levels. Login to comment
164 Further studies are required to understand the role of ABCA1 and the R230C variant in adipocytes. Login to comment
167 In addition to these previously described associations, we found a significant association of R230C with obesity, and thus we sought an association with the metabolic syndrome. Login to comment
169 Interestingly, although 21.7% of R230C heterozygotes had metabolic syndrome, all eight C230C homozygotes met both IDF and ATP-III criteria for metabolic syndrome. Login to comment
171 We also found a significant association of R230C with type 2 diabetes in the Mexican-Mestizo population. Login to comment
178 The high frequencies of type 2 diabetes and R230C in the Mexican-Mestizo population provide a unique opportunity to more thoroughly analyze this association in the diabetic population. Login to comment
181 Even though Amerindian ancestry may be considered a risk factor for these metabolic traits, the associations of R230C with obesity, the metabolic syndrome, and type 2 diabetes remained significant after adjusting for admixture. Login to comment
182 Thus, it appears that ABCA1 R230C or some other variant in linkage disequilibrium with it represents a significant risk factor for low HDL levels, obesity, and obesity-related comorbidities. Login to comment
183 High prevalence of R230C in Amerindian populations. Login to comment
185 The high frequency of R230C in the Mexican population suggests that this could be one of several gene variants contributing to this genetic susceptibility. Login to comment
186 In most Mexican Amerindian populations analyzed, the allele and genotype frequencies of R230C were approximately twofold higher than in Mexican Mestizos, as would be expected because of the admixture. Login to comment
187 Interestingly, R230C seems to be found exclusively in Amerindian and Amerindian-derived populations such as Mexican Mestizos. Login to comment
190 Nevertheless, the notoriously higher frequency of R230C in Amerindians of Mexico suggests, first, a much more remote origin, possibly among the first humans crossing the Be¨ring Strait, and, second, that R230C may have somehow been selected in Amerindians. Login to comment
191 Among the possible selective advantages are 1) R230C could be an energy-saving allele favorable in famine or insufficient food availability and 2) based on the finding that a homozygous ABCA1 gene deletion confers complete resistance against cerebral malaria in mice (49), it is possible to speculate that R230C could also confer protection against certain infectious and/or thrombotic disorders involving vesiculation. Login to comment
193 In conclusion, the R230C variant is apparently a marker informative for Amerindian ancestry, which is also significantly associated with low HDL cholesterol levels, obesity, and obesity-related comorbidities, although further studies are required to confirm these associations. Login to comment
194 Functional studies both in vitro and in vivo are required to further understand the role of ABCA1 and the R230C variant in these metabolic traits. Login to comment

[hide] Variations on a gene: rare and common variants in ... Annu Rev Nutr. 2006;26:105-29. Brunham LR, Singaraja RR, Hayden MR
Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.
Annu Rev Nutr. 2006;26:105-29., [PMID:16704350]

Abstract [show]
Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.

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605 Many of these variants have been studied in relationship to their association with HDL cholesterol levels and atherosclerosis (11, 15, 22, 27, 28, 38, TABLE 4 Nonsynonymous single-nucleotide polymorphisms (SNPs) in ABCA1 SNP id Nucleotidea Amino acidb Observed heterozygosity rs2230806 G969A R219K 0.488 rs9282541 C1001T R230C 0.029 rs9282543 T1509C V399A 0.020 rs4131108 A1556C M415L - rs13306068 A1949G I546V - rs2066718 G2624A V771M 0.074 rs2472458 G2804A D831N - rs4149313 A2962G I883M - rs2482437 C3326T E1005K - rs13306072 G3473A V1054I - rs13306073 G3599A V1096I - rs1997618 T4977C I1555T - rs2230808 A5073G K1587R 0.480 rs1883024 T5256C L1648P - - C5505G S1731C - a Nucleotide position is with respect to NM 005502. b Amino acid position is with respect to NP 005493. Login to comment

[hide] Accurate prediction of the functional significance... PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30. Brunham LR, Singaraja RR, Pape TD, Kejariwal A, Thomas PD, Hayden MR
Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.
PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30., [PMID:16429166]

Abstract [show]
The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation.

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48 This SNP has been reported to be associated with decreased HDL cholesterol and increased severity of atherosclerosis in Table 1. subPSEC Scores and Probability of Functional Impairment (Pdeleterious) for ABCA1 Mutations and SNPs Mutations SNPs Variant SubPSEC Pdeleterious Variant subPSEC Pdeleterious P85L À4.62 0.83 R219K À0.57 0.08 H160F À2.79 0.45 V399A À2.26 0.32 R230C À4.27 0.78 V771M À2.86 0.46 A255T À1.81 0.23 T774P À1.99 0.27 E284K À2.34 0.34 K776N À3.53 0.63 Y482C À4.21 0.77 V825I À1.06 0.13 R587W À6.04 0.95 I883M À1.38 0.17 W590S À5.19 0.9 E1172D À1.96 0.26 W590L À4.48 0.82 R1587K À0.58 0.08 Q597R À7.15 0.98 S1731C À4.21 0.77 T929I À4.29 0.78 N935H À8.54 1 N935S À7.53 0.99 A937V À6.6 0.97 A1046D À7.52 0.99 M1091T À3.56 0.64 D1099Y À6.09 0.96 D1289N À2.48 0.37 L1379F À3.81 0.69 C1477R À5.44 0.92 S1506L À5.17 0.9 N1611D À5.69 0.94 R1680W À6.02 0.95 V1704D À3.21 0.55 N1800H À4.23 0.77 R1901S À5.06 0.89 F2009S À2.73 0.43 R2081W À8.08 0.99 P2150L À2.88 0.47 Q2196H À2.74 0.43 DOI: 10.1371/journal.pgen.0010083.t001 PLoS Genetics | www.plosgenetics.org December 2005 | Volume 1 | Issue 6 | e83 0740 Accurate Prediction of ABCA1 Variants Synopsis A major goal of human genetics research is to understand how genetic variation leads to differences in the function of genes. Login to comment

[hide] Familial HDL deficiency due to ABCA1 gene mutation... Atherosclerosis. 2004 Feb;172(2):309-20. Pisciotta L, Hamilton-Craig I, Tarugi P, Bellocchio A, Fasano T, Alessandrini P, Bon GB, Siepi D, Mannarino E, Cattin L, Averna M, Cefalu AB, Cantafora A, Calandra S, Bertolini S
Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders.
Atherosclerosis. 2004 Feb;172(2):309-20., [PMID:15019541]

Abstract [show]
Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with premature coronary artery disease (pCAD), had a combination of genetic defects. Besides being heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q substitution in apolipoprotein B and the third was a carrier of N291S substitution in lipoprotein lipase. By extending family studies we identified 17 heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these subjects were 38.3 and 36.9% lower than in unaffected family members and similar to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1 mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked and (ii) there may be a selection bias in genotyping towards carriers of ABCA1 mutations who have pCAD possibly related to a combination of genetic and environmental cardiovascular risk factors.

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208 Interestingly, a cysteine for arginine substitution in the first extracellular loop (R230C) was reported in three Oji-Cree subjects with very low plasma HDL levels [11]. Login to comment
207 Interestingly, a cysteine for arginine substitution in the first extracellular loop (R230C) was reported in three Oji-Cree subjects with very low plasma HDL levels [11]. Login to comment

[hide] Efflux and atherosclerosis: the clinical and bioch... Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32. Epub 2003 May 22. Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR
Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene.
Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32. Epub 2003 May 22., [PMID:12763760]

Abstract [show]
Approximately 50 mutations and many single nucleotide polymorphisms have been described in the ABCA1 gene, with mutations leading to Tangier disease and familial hypoalphalipoproteinemia. Homozygotes and heterozygotes for mutations in ABCA1 display a wide range of phenotypes. Identification of ABCA1 as the molecular defect in these diseases has allowed for ascertainment based on genetic status and determination of genotype-phenotype correlations and has permitted us to identify mutations conferring a range of severity of cellular, biochemical, and clinical phenotypes. In this study we review how genetic variation at the ABCA1 locus affects its role in the maintenance of lipid homeostasis and the natural progression of atherosclerosis.

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83 TABLE 2. Conservation of Amino Acid Residues Mutated in Humans Mutation H. sapiens M. musculus G. gallus D. melanogaster C. elegans P85L P P P ⅐ ⅐ ⅐ P R230C R R R P G A255T A A S ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ R587W R R R ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ W590S W W W R Q Q597R Q Q Q Q Q ⌬L693 L L L L L T929I T T T T T N935S/H N N N N N A937V A A A A A A1046D A A A A A M1091T M M M M M D1099Y D D D D D D1289L/N D D D D D C1477R C C C ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ S1506L S S S ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ N1611D N N N N S R1680W R R R R R N1800H N N N A W F2009S F F F I M R2081W R R R R R P2150L P P P R N ⌬E1893 E E E D S ⌬D1894 D D D D D Twenty-three of 24 (95.83%) amino acids affected by mutations are conserved with G. gallus, reflecting the functional importance of these residues. Login to comment
75 TABLE 2. Conservation of Amino Acid Residues Mutated in Humans Mutation H. sapiens M. musculus G. gallus D. melanogaster C. elegans P85L P P P ዼ ዼ ዼ P R230C R R R P G A255T A A S ዼ ዼ ዼ ዼ ዼ ዼ R587W R R R ዼ ዼ ዼ ዼ ዼ ዼ W590S W W W R Q Q597R Q Q Q Q Q èc;L693 L L L L L T929I T T T T T N935S/H N N N N N A937V A A A A A A1046D A A A A A M1091T M M M M M D1099Y D D D D D D1289L/N D D D D D C1477R C C C ዼ ዼ ዼ ዼ ዼ ዼ S1506L S S S ዼ ዼ ዼ ዼ ዼ ዼ N1611D N N N N S R1680W R R R R R N1800H N N N A W F2009S F F F I M R2081W R R R R R P2150L P P P R N èc;E1893 E E E D S èc;D1894 D D D D D Twenty-three of 24 (95.83%) amino acids affected by mutations are conserved with G. gallus, reflecting the functional importance of these residues. Login to comment

[hide] Genetics of HDL regulation in humans. Curr Opin Lipidol. 2003 Jun;14(3):273-9. Miller M, Rhyne J, Hamlette S, Birnbaum J, Rodriguez A
Genetics of HDL regulation in humans.
Curr Opin Lipidol. 2003 Jun;14(3):273-9., [PMID:12840658]

Abstract [show]
PURPOSE OF REVIEW: To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states. RECENT FINDINGS: The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future. SUMMARY: Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.

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64 TD 1051 G/A 7 R219K extracellular [67,68] FHA 1083 C/T 7 R230C extracellular [70] FHA 1158 G/A 8 A255T extracellular [75.] Login to comment

[hide] ABC transporter genes and risk of type 2 diabetes:... Diabetes Care. 2012 Dec;35(12):2600-6. doi: 10.2337/dc12-0082. Epub 2012 Nov 8. Schou J, Tybjaerg-Hansen A, Moller HJ, Nordestgaard BG, Frikke-Schmidt R
ABC transporter genes and risk of type 2 diabetes: a study of 40,000 individuals from the general population.
Diabetes Care. 2012 Dec;35(12):2600-6. doi: 10.2337/dc12-0082. Epub 2012 Nov 8., [PMID:23139370]

Abstract [show]
OBJECTIVE: Alterations of pancreatic beta-cell cholesterol content may contribute to beta-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATP-binding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1). Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown. RESEARCH DESIGN AND METHODS: We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415). RESULTS: Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively). CONCLUSIONS: Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1.

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107 In a case-control study of 244 patients with type 2 diabetes versus 202 nondiabetic control subjects, ABCA1 R230C was reported to associate with type 2 diabetes in a Mexican-Mestizo population (9). Login to comment

[hide] The ABCA1 gene R230C variant is associated with de... PLoS One. 2012;7(11):e49285. doi: 10.1371/journal.pone.0049285. Epub 2012 Nov 9. Villarreal-Molina T, Posadas-Romero C, Romero-Hidalgo S, Antunez-Arguelles E, Bautista-Grande A, Vargas-Alarcon G, Kimura-Hayama E, Canizales-Quinteros S, Juarez-Rojas JG, Posadas-Sanchez R, Cardoso-Saldana G, Medina-Urrutia A, Gonzalez-Salazar Mdel C, Martinez-Alvarado R, Jorge-Galarza E, Carnevale A
The ABCA1 gene R230C variant is associated with decreased risk of premature coronary artery disease: the genetics of atherosclerotic disease (GEA) study.
PLoS One. 2012;7(11):e49285. doi: 10.1371/journal.pone.0049285. Epub 2012 Nov 9., [PMID:23152888]

Abstract [show]
BACKGROUND: ABCA1 genetic variation is known to play a role in HDL-C levels and various studies have also implicated ABCA1 variation in cardiovascular risk. The functional ABCA1/R230C variant is frequent in the Mexican population and has been consistently associated with low HDL-C concentrations. Although it has been associated with other cardiovascular risk factors such as obesity and type 2 diabetes mellitus, it is not known whether it is associated with coronary artery disease (CAD). AIM: The purpose of the study was to analyze whether the ABCA1/R230C variant is associated with premature CAD in a case-control association study (GEA or Genetics of Atherosclerotic Disease), and to explore whether BMI modulates the effect of the C230 allele on other metabolic traits using a population-based design. RESULTS: The C230 allele was significantly associated with both lower HDL-C levels and a lower risk of premature CAD as compared to controls (OR = 0.566; P(add) = 1.499x10(-5)). In addition, BMI modulated the effect of R230C on body fat distribution, as the correlation between BMI and visceral to subcutaneous adipose tissue (a metric of the propensity to store fat viscerally as compared to subcutaneously) was negative in RR homozygous individuals, but positive in premenopausal women bearing the C230 allele, with a statistically significant interaction (P = 0.005). BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036). CONCLUSION: This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. C230 was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C interactions were observed for different metabolic traits. These interactions may help explain inconsistencies in associations, and underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise and other environmental factors.

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0 The ABCA1 Gene R230C Variant Is Associated with Decreased Risk of Premature Coronary Artery Disease: The Genetics of Atherosclerotic Disease (GEA) Study Teresa Villarreal-Molina1 *, Carlos Posadas-Romero2 , Sandra Romero-Hidalgo3 , Erika Antu &#b4; nez-Argu &#a8; elles1 , Araceli Bautista-Grande1 , Gilberto Vargas-Alarco &#b4; n4 , Eric Kimura-Hayama5 , Samuel Canizales-Quinteros6,7 , Juan Gabriel Jua &#b4;rez-Rojas2 , Rosalinda Posadas-Sa &#b4;nchez2 , Guillermo Cardoso-Saldan dc; a2 , A &#b4;da Medina-Urrutia2 , Mar &#b4;a del Carmen Gonza &#b4;lez-Salazar2 , Roc &#b4;o Mart &#b4;nez-Alvarado2 , Esteban Jorge- Galarza2 , Alessandra Carnevale8 1 Laboratorio de Geno &#b4;mica de Enfermedades Cardiovasculares, Instituto Nacional de Medicina Geno &#b4;mica (INMEGEN), Mexico City, Mexico, 2 Departmento de Endocrinolog &#b4;a, Instituto Nacional de Cardiolog &#b4;a ''Ignacio Cha &#b4;vez`` (INCICH), Mexico City, Mexico, 3 Departmento de Geno &#b4;mica Computacional, INMEGEN, Mexico City, Mexico, 4 Departamento de Biolog &#b4;a Molecular, INCICH, Mexico City, Mexico, 5 Departmento de Tomograf &#b4;a Card &#b4;aca, INCICH, Mexico City, Mexico, 6 Departamento de Biolog &#b4;a, Facultad de Qu &#b4;mica, Universidad Nacional Auto &#b4;noma de Me &#b4;xico (UNAM), Mexico City, Mexico, 7 Unidad de Biolog &#b4;a Molecular y Medicina Geno &#b4;mica, Instituto Nacional de Ciencias Me &#b4;dicas y Nutricio &#b4;n ''Salvador Zubira &#b4;n``, Mexico City, Mexico, 8 Direccio &#b4;n de Investigacio &#b4;n, INMEGEN, Mexico City, Mexico Abstract Background: ABCA1 genetic variation is known to play a role in HDL-C levels and various studies have also implicated ABCA1 variation in cardiovascular risk. Login to comment
1 The functional ABCA1/R230C variant is frequent in the Mexican population and has been consistently associated with low HDL-C concentrations. Login to comment
3 Aim: The purpose of the study was to analyze whether the ABCA1/R230C variant is associated with premature CAD in a case-control association study (GEA or Genetics of Atherosclerotic Disease), and to explore whether BMI modulates the effect of the C230 allele on other metabolic traits using a population-based design. Login to comment
5 In addition, BMI modulated the effect of R230C on body fat distribution, as the correlation between BMI and visceral to subcutaneous adipose tissue (a metric of the propensity to store fat viscerally as compared to subcutaneously) was negative in RR homozygous individuals, but positive in premenopausal women bearing the C230 allele, with a statistically significant interaction (P = 0.005). Login to comment
6 BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036). Login to comment
7 Conclusion: This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. Login to comment
8 C230 was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C interactions were observed for different metabolic traits. These interactions may help explain inconsistencies in associations, and underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise and other environmental factors. Login to comment
9 Citation: Villarreal-Molina T, Posadas-Romero C, Romero-Hidalgo S, Antu &#b4;nez-Argu &#a8;elles E, Bautista-Grande A, et al. (2012) The ABCA1 Gene R230C Variant Is Associated with Decreased Risk of Premature Coronary Artery Disease: The Genetics of Atherosclerotic Disease (GEA) Study. Login to comment
20 The R230C variant of the ABCA1 gene is of particular interest in the Americas because it is private to Native American and descendant populations and is frequent in the Mexican-Mestizo population (,10%). Login to comment
24 The purpose of the present study was to analyze whether the ABCA1/R230C variant is associated with premature CAD and subclinical atherosclerosis in a case-control association study: GEA (Genetics of Atherosclerotic Disease). Login to comment
51 The ABCA1/R230C variant (rs9282541) was genotyped using TaqMan assays (ABI Prism 7900HT sequence detection system (Applied Biosystems). Login to comment
58 ANCOVA was used to determine associations between the R230C variant and metabolic variables, adjusting for age, gender, BMI, and HDL-C levels as indicated using additive and dominant models. Login to comment
62 Statistical power to detect association of R230C with premature CAD exceeded 0.80 as estimated with QUANTO software (http://hydra.usc.edu/GxE/). Login to comment
66 Association of ABCA1/R230C with Premature CAD The C230 risk allele frequency was similar in controls and individuals with subclinical atherosclerosis (.106 and.093 respectively), but lower in the premature CAD group (0.072). Login to comment
70 Association of ABCA1/R230C with Metabolic Traits The effect of the C230 risk allele on various metabolic parameters was explored in all individuals recruited initially as controls regardless of their CAC score. Login to comment
81 Predicted values were calculated from regression models containing the ABCA1/R230C variant, BMI and the interaction term, adjusted for age (Figure 3). Login to comment
83 No significant BMI-R230C interactions were observed for LSAR (data not shown). Login to comment
85 BMI and HOMA-IR showed positive and significant correlations in both genders, and no significant differences according to ABCA1/R230C genotype were observed in the entire sample or stratifying by gender (Figure S1, A and Table 2. Login to comment
92 Association of the R230C/ABCA1 variant with premature coronary artery disease and subclinical artherosclerosis. Login to comment
98 In premenopausal women bearing R230C genotypes, this effect showed a modest increase (b = 3.74%; P = 4.961026 ) as compared to R230R homozygous premenopausal women (b = 2.55%; P = 1.2610213 ) (Figure S1, C and D), although the interaction did not reach statistical significance (P = 0.121). Login to comment
99 Predicted values were calculated from regression models containing the ABCA1/R230C variant, BMI and the interaction term in premenopausal women (Figure S1, E and F). Login to comment
105 Predicted TG values were calculated from regression models containing the ABCA1/R230C variant, BMI and the interaction term, adjusted for age (Figure S2, E), and the interaction between BMI and the R230C variant was significant only in women (P = 0.036). Login to comment
108 Association of the R230C/ABCA1 variant with quantitative metabolic parameters. Login to comment
113 Associations of the R230C/ABCA1 variant with metabolic risk factors for coronary artery disease. Login to comment
128 The Interaction of R230C and BMI Affects the Distribution of Abdominal Fat in Premenopausal Women. Lines represent simple linear regressions, blue lines represent RR genotypes and red lines represent C230 risk allele carriers (RC/CC genotypes). Login to comment
133 The results of the present case-control association study is another example of this discrepancy, as the ABCA1/R230C variant was significantly associated with both decreased HDL-C levels and a decreased risk of premature CAD. Login to comment
134 Interestingly, the association with premature CAD was significant with and without adjusting for HDL-C levels as a covariate, suggesting that the effects of ABCA1/R230C on HDL-C levels and the risk of premature CAD are independent. Login to comment
140 Associations with other Metabolic Parameters To date, all reports assessing the effect of the ABCA1/R230C variant on HDL-C concentrations including the present study have consistently shown highly significant associations with decreased HDL-C levels [13-17]. Login to comment
142 Because obesity is associated with many metabolic risk factors for cardiovascular disease, we sought possible explanations for such inconsistencies exploring whether BMI modulates the effect of the R230C variant on several metabolic traits. Login to comment
143 We found no evidence of BMI modulating the effect of ABCA1/ R230C on any of the metabolic parameters explored in men. Login to comment
144 However, some BMI-R230C interactions were observed in women: BMI modulated the effect of this allele on VAT/SAT ratio and HOMA-IR in pre-menopausal women and on TG levels in women regardless of their menopausal status. Login to comment
147 The BMI-R230C interactions observed only in pre-menopausal women suggest that these effects may be estrogen-related. Login to comment
149 The increased risk of these metabolic parameters in pre-menopausal women is again in discrepancy with their risk of CAD, and whether this has to do with other systemic effects of estrogen, and/or with pleiotropic effects of the R230C variant in platelets, endothelium, inflammatory or other cell types remains to be elucidated. Login to comment
152 Predicted visceral to subcutaneous adipose tissue ratio (VAT/SAT) values were calculated from regression models containing the ABCA1/R230C variant, BMI and the interaction term, adjusted for age. Login to comment
155 doi:10.1371/journal.pone.0049285.g003 The R230C allele was associated with T2DM in a case-control association study in the Mexican population and replicated in an independent sample [18]. Login to comment
160 Conclusion This is the first study assessing the effect of the R230C/ABCA1 variant in premature coronary artery disease. Login to comment
161 This variant was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C variant interactions were observed for different metabolic traits. These findings underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise and other environmental factors. Login to comment
166 Predicted HOMA-IR values were calculated from regression models containing the ABCA1/R230C variant, BMI and the interaction term in premenopausal (E) and menopausal women (F). Login to comment
167 (TIF) Figure S2 The interaction of R230C and BMI affects triglyceride levels in women. Lines represent simple linear regressions. Login to comment
171 Predicted triglyceride values (E) were calculated from regression models containing the ABCA1/R230C variant, BMI and the interaction term in women, and the interaction was statistically significant (P = 0.036). Login to comment

[hide] The R230C variant of the ATP binding cassette prot... Metabolism. 2013 May;62(5):638-41. doi: 10.1016/j.metabol.2012.11.006. Epub 2012 Dec 27. Aguilar-Salinas CA, Munoz-Hernandez LL, Cobos-Bonilla M, Ramirez-Marquez MR, Ordonez-Sanchez ML, Mehta R, Medina-Santillan R, Tusie-Luna MT
The R230C variant of the ATP binding cassette protein A1 (ABCA1) gene is associated with a decreased response to glyburide therapy in patients with type 2 diabetes mellitus.
Metabolism. 2013 May;62(5):638-41. doi: 10.1016/j.metabol.2012.11.006. Epub 2012 Dec 27., [PMID:23273975]

Abstract [show]
OBJECTIVE: To test the hypothesis that persons with the R230C allele of ABCA1 show a decreased glycemic response to glyburide. This polymorphism is exclusively found in Ameri-indian populations and is associated with type 2 diabetes. RESEARCH DESIGN AND METHODS: This is a single blind controlled study including participants with type 2 diabetes (fasting glucose levels 126-250 mg/dl and HbA1c 7%-10%) managed with metformin and a lifestyle program. Each person with the risk allele (R230C) was matched by age, gender and BMI to three others with the wild type variant (R230R). Following a four week stabilization period, only participants with a greater than 70% adherence to metformin and a stable body weight were prescribed glyburide therapy for a further 16 weeks. The main outcome variable was the glyburide dose required to achieve treatment goals. RESULTS: No significant difference was observed in the glucose lowering effect of glyburide between subjects with the R230C and R230R alleles. However, the dose of sulfonylurea was significantly higher in the R230C participants compared with the R230R subjects (3.3+/-2.1 vs 6.3+/-5 mg/day, p<0.001). A higher percentage of R230C participants required at least 5mg of glyburide per day to achieve treatment goals. The glyburide dose was determined by the presence of the risk allele, among other factors. CONCLUSIONS: Patients with type 2 diabetes who have the R230C allele of ABCA1 needed a higher dose of glyburide in order to achieve the same glucose lowering effect as that in persons with the wild type variant.

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0 The R230C variant of the ATP binding cassette protein A1 (ABCA1) gene is associated with a decreased response to glyburide therapy in patients with type 2 diabetes mellitus Carlos A. Aguilar-Salinasa, b,Ìe;, Linda Liliana Mu&#f1;oz-Hernandeza , Monica Cobos-Bonillaa , Marcos Rafael Ram&#ed;rez-M&#e1;rqueza , Maria Luisa Ordo&#f1;ez-Sanchezc , Roopa Mehtaa , Roberto Medina-Santillanb , Maria Teresa Tusie-Lunac a Department of Endocrinology and Metabolism. Login to comment
4 To test the hypothesis that persons with the R230C allele of ABCA1 show a decreased glycemic response to glyburide. Login to comment
8 Each person with the risk allele (R230C) was matched by age, gender and BMI to three others with the wild type variant (R230R). Login to comment
12 No significant difference was observed in the glucose lowering effect of glyburide between subjects with the R230C and R230R alleles. Login to comment
13 However, the dose of sulfonylurea was significantly higher in the R230C participants compared with the R230R subjects (3.3&#b1;2.1 vs 6.3&#b1;5 mg/day, p<0.001). Login to comment
14 A higher percentage of R230C participants required at least 5 mg of glyburide per day to achieve treatment goals. Login to comment
17 Patients with type 2 diabetes who have the R230C allele of ABCA1 needed a higher dose of glyburide in order to achieve the same glucose lowering effect as that in persons with the wild type variant. Login to comment
27 One such variant, the R230C allele (rs9282541) is common in the Mexican population; a population-based survey, reported a prevalence of 18.7% among participants [3,4]. Login to comment
29 In addition, two cross-sectional studies have shown that the R230C variant of ABC-A1 is associated with type 2 diabetes. Login to comment
36 In this report, our hypothesis is that persons with type 2 diabetes who have the R230C variant of ABCA1 may have a decreased hypoglycemic response to a sulfonylurea, compared to participants with the wild type variant (R230R). Login to comment
39 One group had the R230C variant of ABC-A1 and the other had the R230R variant. Both groups were matched for gender, age (&#b1;5 years) and BMI (&#b1;2 kg/m2 ). Login to comment
62 The R230C variant was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System, Applied Biosystems). Login to comment
69 Results Our study sample included 17 individuals with the R230C variant and 68 subjects with the R230R variant. Both groups were successfully matched by age, gender and body mass index (Table 1). Login to comment
77 However, individuals with the R230C variant required a significantly higher glyburide dose (3.3&#b1;2.1 vs 6.3&#b1;5 mg/day, p<0.001) to achieve the same glucose lowering effect as persons with the wild type variant. Login to comment
78 A glyburide doseࣙ5 mg/ day was more common in the R230C group. Login to comment
83 Discussion Our data show that persons with type 2 diabetes who have the ABCA1 R230C polymorphism require a higher glyburide dose to achieve similar glucose lowering as matched subjects with the wild type variant. Login to comment
85 The R230C allele was independently associated with the glyburide dosage, even after adjusting for FPG, BMI and adherence to therapy. Login to comment
90 This abnormality would occur in the R230C variant individuals as a result of a decrease in ABC-A1 activity [13,14]. Login to comment
93 In addition, the R230C variant is independently associated with lower HDL-C concentrations [4]. Login to comment
94 Since HDL particles may have beneficial effects on beta cell function and survival [15,16], the coexistence of lower HDL-C concentrations may be another mechanism by which the R230C variant is associated with a decreased response to glyburide. Login to comment
99 Additional studies are needed to measure insulin secretory capacity in patients with or without the R230C polymorphism and to elucidate the Table 1 - Clinical and biochemical parameters in R230C carriers of ATP-binding cassette transporter A1 gene and their controls (R230R) at baseline. Login to comment
100 Total (n=85) R230R (n=70) R230C (n=17) P value Age (years) 53.6&#b1;11 54.4&#b1;10 50.2&#b1;12 0.166 Females (n (%)) 55 (64.7) 44 (64.7) 11 (64.7) 1.0 Waist circumference (cm) 99&#b1;10 99&#b1;10 96&#b1;7 0.211 Time since diagnosis (years) 6.1&#b1;5.4 6.0&#b1;5.4 6.4&#b1;5.7 0.760 Body mass index (kg/m2 ) 30.3&#b1;6 30.4&#b1;6 30.1&#b1;4 0.827 Systolic blood pressure 120&#b1;13 121&#b1;14 118&#b1;10 0.375 Diastolic blood pressure 75&#b1;8 76&#b1;8 74&#b1;9 0.284 Fasting glycemia a (mg/dl) 150&#b1;54 146&#b1;52 163&#b1;62 0.266 Fasting insulin (mU/ml)a 12&#b1;7 12&#b1;7 11&#b1;7 0.616 HbA1c (%)a 8.9&#b1;1.5 8.7&#b1;1.5 9.4&#b1;1.7 0.086 Triglycerides (mg/dl)a 195&#b1;135 189&#b1;129 220&#b1;160 0.399 Cholesterol (mg/dl)a 182&#b1;51 188&#b1;53 171&#b1;40 0.209 HDL-cholesterol (mg/dl)a 43.6&#b1;12 44.7&#b1;13 38.9&#b1;7.9 0.093 Apolipoprotein B (mg/dl) a 106&#b1;31 107&#b1;30 102&#b1;36 0.494 a After the run-in period. Login to comment
101 Table 2 - Glycemic response to glyburide therapy of R230C carriers of the ATP-binding cassette transporter A1 gene and their controls (R230R). Login to comment
102 Total (n=85) R230R (n=68) R230C (n=17) P value Percent change in fasting plasma glucose (%) -10.9&#b1;22 -11.8&#b1;23 -7.7&#b1;18 0.502 Absolute change in HbA1c (% units) -2.2&#b1;1.4 -2.2&#b1;1.5 -2.0&#b1;1.3 0.725 Mean glyburide dosage (mg/day) 3.9&#b1;3.1 3.3&#b1;2.1 6.3&#b1;5.0 0.001 Percentage of cases with glyburideࣙ5 mg/day (% (n)) 34.1 (29) 30.8 (21) 47 (8) 0.020 Percentage of cases with HbA1c <7% (%(n)) 60 (51) 63.2 (43) 47 (8) 0.411 Percentage of cases with fasting plasma glucose <110 mg/dl (%(n)) 43.5 (37) 42.6 (29) 47.9 (8) 0.438 640 M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 2 ( 2 0 1 ) 6 3 8 - 6 4 1 mechanisms which explain the higher sulfonylurea requirement in the R230C group. Login to comment
122 [4] Aguilar-Salinas CA, Canizales-Quinteros S, Rojas-Mart&#ed;nez R, et al. The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study. Login to comment
124 [5] Villarreal-Molina MT, Aguilar-Salinas CA, Rodr&#ed;guez-Cruz M, et al. The ABCA1 R230C variant affects HDL cholesterol levels and body mass index in the Mexican population: association with obesity and obesity-related comorbidities. Login to comment
126 [6] Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, et al. Association of the ABCA1 R230C variant with early-onset type 2 diabetes in the Mexican population. Login to comment

[hide] Genomic study in Mexicans identifies a new locus f... J Med Genet. 2013 May;50(5):298-308. doi: 10.1136/jmedgenet-2012-101461. Epub 2013 Mar 15. Weissglas-Volkov D, Aguilar-Salinas CA, Nikkola E, Deere KA, Cruz-Bautista I, Arellano-Campos O, Munoz-Hernandez LL, Gomez-Munguia L, Ordonez-Sanchez ML, Reddy PM, Lusis AJ, Matikainen N, Taskinen MR, Riba L, Cantor RM, Sinsheimer JS, Tusie-Luna T, Pajukanta P
Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci.
J Med Genet. 2013 May;50(5):298-308. doi: 10.1136/jmedgenet-2012-101461. Epub 2013 Mar 15., [PMID:23505323]

Abstract [show]
BACKGROUND: The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. METHODS AND FINDINGS: We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4361), and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein gene (p=2.43x10(-08)). Furthermore, three European loci for TGs (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We used cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalised to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. CONCLUSIONS: This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; used the interpopulation heterogeneity to significantly restrict three previously known European GWA signals, and surveyed whether the European lipid GWA SNPs extend to the Mexican population.

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160 The functionally important missense variant rs9282541 in ABCA1 (R230C) indeed seems to be exclusive to Amerindian-derived populations such as Mexicans.35 However, the frequencies of the independent SNPs rs2036402 near TIMD4 and rs4149310 near ABCA1 are substantially lower in the HapMapIII CEU panel than in Mexicans. These interpopulation differences in allele frequency can lead to association signals at different SNPs in different populations which do not necessarily mean that the causal variant is also population specific. Login to comment

[hide] Trans-ethnic fine-mapping of lipid loci identifies... PLoS Genet. 2013 Mar;9(3):e1003379. doi: 10.1371/journal.pgen.1003379. Epub 2013 Mar 21. Wu Y, Waite LL, Jackson AU, Sheu WH, Buyske S, Absher D, Arnett DK, Boerwinkle E, Bonnycastle LL, Carty CL, Cheng I, Cochran B, Croteau-Chonka DC, Dumitrescu L, Eaton CB, Franceschini N, Guo X, Henderson BE, Hindorff LA, Kim E, Kinnunen L, Komulainen P, Lee WJ, Le Marchand L, Lin Y, Lindstrom J, Lingaas-Holmen O, Mitchell SL, Narisu N, Robinson JG, Schumacher F, Stancakova A, Sundvall J, Sung YJ, Swift AJ, Wang WC, Wilkens L, Wilsgaard T, Young AM, Adair LS, Ballantyne CM, Buzkova P, Chakravarti A, Collins
Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
PLoS Genet. 2013 Mar;9(3):e1003379. doi: 10.1371/journal.pgen.1003379. Epub 2013 Mar 21., [PMID:23555291]

Abstract [show]
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 x 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

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234 Reported functional variants [ref] Reported functional variants on Metabochip Variants with strongest association at a signal Signal Ethnic group* MAF Notes PCSK9: rs28362286 (C679X) [22] Yes rs28362286 1st AA 0.009 Same variant PCSK9: rs28362263 (A443T) [29] Yes rs28362263 2nd AA 0.097 Same variant PCSK9: rs28362261 (N425S) [30] Yes rs28362261 3rd AA 0.017 Same variant PCSK9: rs67608943 (Y142X) [22] Yes rs67608943 4th AA 0.004 Same variant PCSK9: rs72646508 (L253F) [22] Yes rs72646508 5th AA 0.003 Same variant APOE: rs7412 (R176C) [23] Yes rs7412 1st AA, ASN, EUR 0.056-0.110 Same variant APOE: rs769455 (R163C) [31] Yes rs769455 2nd AA 0.020 Same variant APOA5: rs3135506 (S19W) [26] Yes rs3135506 1st AA 0.058 Same variant APOA5: rs651821(-3A.G) [32] Yes rs651821 1st ASN 0.275 Same variant APOA5: rs2075291 (G185C) [25] Yes rs2075291 2nd ASN 0.064 Same variant GCKR: rs1260326 (L446P) [28] Yes rs1260326 1st AA, EUR 0.149-0.350 Same variant SORT1: rs12740374 [18] Yes rs12740374 1st AA 0.247 Same variant CETP: rs17231520 [33] Yes rs17231520 3rd AA 0.069 Same variant LIPC: rs2070895 [34] Proxy: rs1077834 (LD r2 = 1.00) rs1077834 1st, 2nd AA, EUR 0.481 LD r2 = 1.00 APOB: rs7575840 [35] Yes rs934198 1st EUR 0.298 LD r2 = 0.98 LPL: rs328 (S447X) [36] Yes rs1803924 1st ASN 0.095 LD r2 = 0.96 LDLR: rs688 (N591N) [37] Yes rs73015011, rs112898275 1st AA, EUR ---- LD r2 ,0.01 LPL: rs1801177 (D9N) [38] Yes rs75551077, rs15285 1st AA, EUR ---- LD r2 ,0.02 HMGCR: rs3761740 (-911C.A) [39] Proxy: rs17238330 (LD r2 = 1.00) rs12916 1st EUR ---- LD r2 ,0.20 LDLR: -139C.G [40] No ---- ---- ---- ---- ---- LPL: rs268 (N291S) [41] No ---- ---- ---- ---- ---- ABCA1: rs9282541 (R230C) [42] No ---- ---- ---- ---- ---- ABCA1: rs2066715 (V825I) [43] No ---- ---- ---- ---- ---- LCAT: rs28940887(R159W) [44] No ---- ---- ---- ---- ---- PLTP: R235W [45] No ---- ---- ---- ---- ---- LIPG: rs77960347 (A396S) [46] No ---- ---- ---- ---- ---- LIPG: rs34474737 [47] No ---- ---- ---- ---- ---- *AA, African American; EUR, European; ASN, East Asian. Login to comment

[hide] Myeloid cell-specific ABCA1 deletion does not wors... J Lipid Res. 2013 Oct;54(10):2708-17. doi: 10.1194/jlr.M038943. Epub 2013 Jul 27. Zhu X, Chung S, Bi X, Chuang CC, Brown AL, Liu M, Seo J, Cuffe H, Gebre AK, Boudyguina E, Parks JS
Myeloid cell-specific ABCA1 deletion does not worsen insulin resistance in HF diet-induced or genetically obese mouse models.
J Lipid Res. 2013 Oct;54(10):2708-17. doi: 10.1194/jlr.M038943. Epub 2013 Jul 27., [PMID:23894207]

Abstract [show]
Obesity-associated low-grade chronic inflammation plays an important role in the development of insulin resistance. The membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1) promotes formation of nascent HDL particles. ABCA1 also dampens macrophage inflammation by reducing cellular membrane cholesterol and lipid raft content. We tested the hypothesis that myeloid-specific ABCA1 deletion may exacerbate insulin resistance by increasing the obesity-associated chronic low-grade inflammation. Myeloid cell-specific ABCA1 knockout (MSKO) and wild-type (WT) mice developed obesity, insulin resistance, mild hypercholesterolemia, and hepatic steatosis to a similar extent with a 45% high-fat (HF) diet feeding or after crossing into the ob/ob background. Resident peritoneal macrophages and stromal vascular cells from obese MSKO mice accumulated significantly more cholesterol. Relative to chow, HF diet markedly induced macrophage infiltration and inflammatory cytokine expression to a similar extent in adipose tissue of WT and MSKO mice. Among pro-inflammatory cytokines examined, only IL-6 was highly upregulated in MSKO-ob/ob versus ob/ob mouse peritoneal macrophages, indicating a nonsignificant effect of myeloid ABCA1 deficiency on obesity-associated chronic inflammation. In conclusion, myeloid-specific ABCA1 deficiency does not exacerbate obesity-associated low-grade chronic inflammation and has minimal impact on the pathogenesis of insulin resistance in both HF diet-induced and genetically obese mouse models.

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237 The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. Login to comment
240 Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population. Login to comment

[hide] ATP-binding cassette transporter A1: from metaboli... Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17. Koldamova R, Fitz NF, Lefterov I
ATP-binding cassette transporter A1: from metabolism to neurodegeneration.
Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17., [PMID:24844148]

Abstract [show]
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of high density lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer's disease (AD). A series of reports have revealed a significant impact of ABCA1 on Abeta deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.

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948 A highly frequent non-synonymous variant of ABCA1 (R230C) was identified in a Mexican population and shown to associate with obesity and type 2 diabetes (Villarreal-Molina et al., 2008). Login to comment

[hide] Effects of R219K polymorphism of ATP-binding casse... Biol Res. 2014 Mar 26;47:4. doi: 10.1186/0717-6287-47-4. Liu H, Lin J, Zhu X, Li Y, Fan M, Zhang R, Fang D
Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth.
Biol Res. 2014 Mar 26;47:4. doi: 10.1186/0717-6287-47-4., [PMID:25027185]

Abstract [show]
BACKGROUND: Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 +/- 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method. RESULTS: The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype. CONCLUSIONS: These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.

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192 Aguilar-Salinas CA, Mu&#f1;oz-Hernandez LL, Cobos-Bonilla M, Ram&#ed;rez-M&#e1;rquez MR, Ordo&#f1;ez-Sanchez ML, Mehta R, Medina-Santillan R, Tusie-Luna MT: The R230C variant of the ATP binding cassette protein A1 (ABCA1) gene is associated with a decreased response to glyburide therapy in patients with type 2 diabetes mellitus. Login to comment

[hide] Diabetes susceptibility in Mayas: Evidence for the... Gene. 2015 Jul 1;565(1):68-75. doi: 10.1016/j.gene.2015.03.065. Epub 2015 Mar 31. Lara-Riegos JC, Ortiz-Lopez MG, Pena-Espinoza BI, Montufar-Robles I, Pena-Rico MA, Sanchez-Pozos K, Granados-Silvestre MA, Menjivar M
Diabetes susceptibility in Mayas: Evidence for the involvement of polymorphisms in HHEX, HNF4alpha, KCNJ11, PPARgamma, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes.
Gene. 2015 Jul 1;565(1):68-75. doi: 10.1016/j.gene.2015.03.065. Epub 2015 Mar 31., [PMID:25839936]

Abstract [show]
Association of type 2 diabetes (T2D) with common variants in HHEX, HNF4alpha, KCNJ11, PPARgamma, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes have been reported, mainly in populations of European and Asian ancestry and to a lesser extent in Latin Americans. Thus, we aimed to investigate the contribution of rs1111875 (HHEX), rs1800961 (HNF4alpha), rs5219 (KCNJ11), rs1801282 (PPARgamma), rs10811661 (CDKN2A/2B), rs13266634 (SLC30A8), rs12779790 (CDC123/CAMK1D), rs7903146 (TCF7L2), rs9282541 (ABCA1) and rs13342692 (SLC16A11) polymorphisms in the genetic background of Maya population to associate their susceptibility to develop T2D. This is one of the first studies designed specifically to investigate the inherited component of T2D in the indigenous population of Mexico. SNPs were genotyped by allelic discrimination method in 575 unrelated Maya individuals. Two SNPs rs10811661 and rs928254 were significantly associated with T2D after adjusting for BMI; rs10811661 in a recessive and rs9282541 in a dominant model. Additionally, we found phenotypical alterations associated with genetic variants: HDL to rs9282541 and insulin to rs13342692. In conclusion, these findings support an association of genetic polymorphisms to develop T2D in Maya population.

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132 In a previous report the association of the variant R230C with T2D in Mexican mestizos was informed, with a variant frequency of 24.5%. Login to comment

[hide] Novel association of the R230C variant of the ABCA... Arch Med Res. 2015 Aug;46(6):495-501. doi: 10.1016/j.arcmed.2015.07.008. Epub 2015 Aug 6. Gamboa-Melendez MA, Galindo-Gomez C, Juarez-Martinez L, Gomez FE, Diaz-Diaz E, Avila-Arcos MA, Avila-Curiel A
Novel association of the R230C variant of the ABCA1 gene with high triglyceride levels and low high-density lipoprotein cholesterol levels in Mexican school-age children with high prevalence of obesity.
Arch Med Res. 2015 Aug;46(6):495-501. doi: 10.1016/j.arcmed.2015.07.008. Epub 2015 Aug 6., [PMID:26256050]

Abstract [show]
BACKGROUND AND AIMS: Metabolic syndrome (MetS) is a disorder that includes a cluster of several risk factors for the development of type 2 diabetes and cardiovascular disease. The R230C variant of the ABCA1 gene has been associated with low HDL-cholesterol in several studies, but its association with MetS in children remains to be determined. The aim of this study was to analyze the association of the R230C variant with MetS and other metabolic traits in school-aged Mexican children. METHODS: The study was performed in seven urban primary schools in the State of Mexico. Four hundred thirty-two Mexican school-age children 6-13 years old were recruited. MetS was identified using the International Diabetes Federation definition. The R230C variant of the ABCA1 gene was genotyped to seek associations with MetS and other metabolic traits. RESULTS: The prevalence of MetS was 29% in children aged 10-13 years. The R230C variant was not associated with MetS (OR = 1.65; p = 0.139). Furthermore, in the whole population, the R230C variant was associated with low HDL-cholesterol levels (beta coefficient = -3.28, p <0.001). Interestingly, in the total population we found a novel association of this variant with high triglyceride levels (beta coefficient = 14.34; p = 0.027). CONCLUSIONS: We found a new association of the R230C variant of the ABCA1 gene with high triglyceride levels. Our findings also replicate the association of this variant with low HDL-cholesterol levels in Mexican school-age children.

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0 ORIGINAL ARTICLE Novel Association of the R230C Variant of the ABCA1 Gene with High Triglyceride Levels and Low High-density Lipoprotein Cholesterol Levels in Mexican School-age Children with High Prevalence of Obesity Marco Alberto Gamboa-Mel endez,a Carlos Galindo-G omez,a Liliana Ju arez-Mart nez,a F. Enrique G omez,b Eulises Diaz-Diaz,c Marco Antonio Avila-Arcos,a and Abelardo Avila-Curiela a Direcci on de Nutrici on, b Departamento de Fisiolog a de la Nutrici on, c Departamento de Biolog a de la Reproducci on, Instituto Nacional de Ciencias M edicas y Nutrici on Salvador Zubir an, M exico, D.F., Mexico Received for publication September 28, 2014; accepted July 31, 2015 (ARCMED-D-14-00546). Login to comment
3 The R230C variant of the ABCA1 gene has been associated with low HDL-cholesterol in several studies, but its association with MetS in children remains to be determined. Login to comment
4 The aim of this study was to analyze the association of the R230C variant with MetS and other metabolic traits in school-aged Mexican children. Login to comment
9 The R230C variant of the ABCA1 gene was genotyped to seek associations with MetS and other metabolic traits. Login to comment
12 The R230C variant was not associated with MetS (OR 5 1.65; p 5 0.139). Login to comment
13 Furthermore, in the whole population, the R230C variant was associated with low HDL-cholesterol levels (b coefficient 5 3.28, p !0.001). Login to comment
16 We found a new association of the R230C variant of the ABCA1 gene with high triglyceride levels. Login to comment
27 In the Mexican population, the nonsynonymous R230C variant (rs9282541) of the ABCA1 gene has been consistently associated with low HDL-cholesterol, whereas in some studies it has been associated with obesity and MetS (6e8). Login to comment
29 However, there has been only one report studying the R230C variant in children, which found an association between R230C and low HDL-cholesterol in school-aged children (10). Login to comment
30 In the present study we evaluated the R230C variant of the ABCA1 gene and its relationship to MetS and its components in a population of children attending public elementary schools in the State of Mexico where overweight and obesity are prevalent. Login to comment
56 The R230C variant of the ABCA1 gene was genotyped using the TaqMan probe (Perkin-Elmer, Waltham, MA) specifically designed for SNP rs9282541 using the Rotor-Gene Q 5-Plex thermal cycler with high-resolution melting (HRM) channel (Qiagen). Login to comment
61 Differences in anthropometric, clinical, and metabolic characteristics of the study population were compared using the Kruskal-Wallis test for continuous variables and c2 test for categorical variables according to age group and R230C genotype. Login to comment
63 The association between the R230C variant and MetS was analyzed by logistic regression models adjusted for age, sex, BMI z-score, and socioeconomic status. Login to comment
64 The association between the R230C variant and quantitative variables was analyzed using multiple linear regression models adjusted for age, sex, socioeconomic status, and BMI z-score when applicable. Login to comment
73 We evaluated the R230C variant and its relationship with MetS and its components. Login to comment
75 Interestingly, an association of the R230C variant with hypoalphalipoproteinemia (OR 5 2.92, p 5 0.001) was shown only in children aged 6e9 years Table 1. Login to comment
80 Median triglyceride concentrations have higher values in children who carry genotypes containing the risk allele (R230C and C230C). Login to comment
81 In addition, we found a statistically significant association of the R230C variant with low HDL-cholesterol levels ( p !0.001); our data imply that for every risk allele unit of this R230C variant there is a decrease of 3.28 mg/dl in plasma HDL-cholesterol levels (Table 4). Login to comment
84 Finally, R230C was not associated with any of the other quantitative traits evaluated (Table 4). Login to comment
87 Therefore, we evaluated whether the non-synonymous R230C variant (rs9282541) of the ABCA1 gene was associated with MetS and whether we could replicate its association with low HDL-cholesterol in a population of children in public elementary schools of the State of Mexico. Login to comment
88 We found a novel association of R230C variant with high triglyceride Table 2. Login to comment
89 Analysis of association of R230C variant abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, and hypoalphalipoproteinemia by age groups TRAITa Risk allele frequency (T) Children aged 6e9 years, n [ 225 Children aged 10e13 years, n [ 207 All, n [ 432 Without trait, n [ 275 With trait, n [ 157 OR (95% CI) p OR (95% CI) p AOb 0.119 0.098 0.128 1.31 (0.69e2.49) 0.404 1.16 (0.59e2.30) 0.665 Hypertension 0.119 0.124 0.078 0.40 (0.10e1.65) 0.203 0.80 (0.30e2.14) 0.650 Hyperglycemia 0.119 0.120 0.118 0.99 (0.46e2.15) 0.983 0.93 (0.47e1.87) 0.846 Hypertriglyceridemia 0.119 0.103 0.153 1.55 (0.85e2.81) 0.152 1.39 (0.73e2.65) 0.318 Hypoalphalipoproteinemia 0.119 0.081 0.167 2.92 (1.56e5.48) 0.001 1.65 (0.88e3.07) 0.117 NA, not applicable; AO, abdominal obesity; OR, odds ratio. Login to comment
94 Clinical and metabolic characteristics of the population stratified by genotype groups TRAIT R230C variant, additive model p R230R (CC) R230C (CT) C230C (TT) BMI (kg/m2 ) 24.2 (21.60e26.84) 24.9 (22.49e27.09) 24.0 (22.92e26.58) 0.575 BMI z-score 2.58 (2.01e2.97) 2.65 (2.31e3.01) 2.70 (2.42e2.91) 0.495 Waist circumference (cm) 81.2 (72.6e87.2) 81.1 (73.04e89.0) 78.8 (74.0e83.0) 0.721 SBP (mmHg) 112.0 (104.0e120.0) 112.0 (104.0e118.0) 102.5 (97.0e107.0) 0.078 DBP (mmHg) 67.0 (61.0e73.0) 65.0 (60.0e72.0) 63.0 (58.0e72.0) 0.267 Glucose (mg/dL) 94.0 (90.0e98.0) 94.0 (91.0e99.0) 93.5 (89.0e97.0) 0.582 Insulin (mU/mL) 14.37 (8.60e20.79) 13.3 (9.56e24.97) 14.7 (10.32e19.70) 0.755 InHOMA (HOMA1-IR) 3.38 (1.95e4.79) 3.12 (2.09e5.82) 3.36 (2.45e4.19) 0.775 HOMA2-% B 117.5 (87.6e157.1) 119.5 (90.5e161.5) 127.3 (90.7e177.2) 0.800 HOMA2-% S 61.7 (43.0e102.5) 66.4 (36.5e91.6) 62.5 (47.5e84.9) 0.752 HOMA2-IR 1.62 (0.98e2.33) 1.51 (1.09e2.74) 1.66 (1.18e2.11) 0.752 Total cholesterol (mg/dL) 163.0 (145.0e184.0) 158.0 (142.0e180.0) 158.5 (129.0e172.0) 0.280 Triglycerides (mg/dL) 118 (80.0e154.0) 126.0 (95.0e199.0) 151 (104.0e172.0) 0.045a HDL-cholesterol (mg/dL) 41.0 (36.0e48.0) 37.0 (33.0e45.0) 34 (33.0e40.0) 0.0002a LDL-cholesterol (mg/dL) 106.0 (90.0e124.0) 103.0 (88.0e126.0) 98.5 (84.0e123.0) 0.827 SBP, systolic blood pressure; DBP, diastolic blood pressure. Medians (25th e75th percentiles) are shown because the data do not show normal distribution. For comparison of groups, non-parametric Kruskal-Wallis test was performed. Statistically significant observations are in bold. a Significant differences of the population stratified by genotype groups. Login to comment
97 However, the R230C variant was not associated with MetS (OR 5 1.65; p 5 0.139). Login to comment
102 In this regard, the R230C variant of the ABCA1 gene was first reported in subjects with familial hypoalphalipoproteinemia in an Oji-Cree population (21). Login to comment
104 In our study, according to the IDF criteria, the R230C variant was not associated with MetS (OR 5 1.65; p 5 0.139). Login to comment
108 This is the second study in which the R230C variant was analyzed in a Mexican school-aged population. Login to comment
111 Acu~ na-Alonzo et al. also found that R230C variant decreases cholesterol efflux by 27% in vitro and showed that it is a functional variant (9). Login to comment
112 Interestingly, we found a novel association of the R230C variant with increased triglyceride levels in the present study. Login to comment
115 However, the effect of BMI on triglyceride levels was greater in women carrying the risk allele of the R230C variant probably (31). Login to comment
117 Although some reports have shown a tendency of higher triglycerides in those subjects with the risk variant genotype in a dominant model (R230C/C230C), their results failed to reach statistical significance (7,8,31,32). Login to comment
126 Although most reports evaluating the R230C variant of the ABCA1 gene did not take into account ancestry, a recent report revealed the importance to consider this factor because Mexico is Table 4. Login to comment
137 In conclusion, our findings confirmed the association of the R230C variant of the ABCA1 gene with low HDL-cholesterol in Mexican school-aged children. Login to comment

[hide] Dietary fat and carbohydrate modulate the effect o... Nutr Metab (Lond). 2015 Nov 16;12:45. doi: 10.1186/s12986-015-0040-3. eCollection 2015. Jacobo-Albavera L, Posadas-Romero C, Vargas-Alarcon G, Romero-Hidalgo S, Posadas-Sanchez R, Gonzalez-Salazar Mdel C, Carnevale A, Canizales-Quinteros S, Medina-Urrutia A, Antunez-Arguelles E, Villarreal-Molina T
Dietary fat and carbohydrate modulate the effect of the ATP-binding cassette A1 (ABCA1) R230C variant on metabolic risk parameters in premenopausal women from the Genetics of Atherosclerotic Disease (GEA) Study.
Nutr Metab (Lond). 2015 Nov 16;12:45. doi: 10.1186/s12986-015-0040-3. eCollection 2015., [PMID:26579206]

Abstract [show]
BACKGROUND: Although the R230C-ATP-binding cassette A1 (ABCA1) variant has been consistently associated with HDL-C levels, its association with diabetes and other metabolic parameters is unclear. Estrogen and dietary factors are known to regulate ABCA1 expression in different tissues. Thus, we aimed to explore whether gender, menopausal status and macronutrient proportions of diet modulate the effect of this variant on various metabolic parameters. METHODS: One thousand five hundred ninety-eight controls from the GEA study were included (787 men, 363 premenopausal women and 448 menopausal women), previously assessed for anthropometric and biochemical measurements and visceral to subcutaneous abdominal fat (VAT/SAT) ratio on computed tomography. Taqman assays were performed for genotyping. Diet macronutrient proportions were assessed using a food frequency questionnaire validated for the Mexican population. Multivariate regression models were constructed to assess the interaction between the proportion of dietary macronutrients and the R230C polymorphism on metabolic parameters. RESULTS: All significant interactions were observed in premenopausal women. Those carrying the risk allele and consuming higher carbohydrate/lower fat diets showed an unfavorable metabolic pattern [lower HDL-C and adiponectin levels, higher VAT/SAT ratio, homeostasis model assessment for insulin resistance (HOMA-IR) and higher gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels]. Conversely, premenopausal women carrying the risk allele and consuming lower carbohydrate/higher fat diets showed a more favorable metabolic pattern (higher HDL-C and adiponectin levels, and lower VAT/SAT ratio, HOMA-IR, GGT and ALP levels). CONCLUSION: This is the first study reporting a gender-specific interaction between ABCA1/R230C variant and dietary carbohydrate and fat percentages affecting VAT/SAT ratio, GGT, ALP, adiponectin levels and HOMA index. Our study confirmed the previously reported gender-specific ABCA1-diet interaction affecting HDL-C levels observed in an independent study. Our results show how gene-environment interactions may help further understand how certain gene variants confer metabolic risk, and may provide information useful to design diet intervention studies.

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0 RESEARCH Open Access Dietary fat and carbohydrate modulate the effect of the ATP-binding cassette A1 (ABCA1) R230C variant on metabolic risk parameters in premenopausal women from the Genetics of Atherosclerotic Disease (GEA) Study Leonor Jacobo-Albavera1 , Carlos Posadas-Romero2 , Gilberto Vargas-Alarc&#f3;n3 , Sandra Romero-Hidalgo4 , Rosalinda Posadas-S&#e1;nchez2 , Mar&#ed;a del Carmen Gonz&#e1;lez-Salazar2 , Alessandra Carnevale5 , Samuel Canizales-Quinteros6 , Aida Medina-Urrutia2 , Erika Ant&#fa;nez-Arg&#fc;elles7 and Teresa Villarreal-Molina7* Abstract Background: Although the R230C-ATP-binding cassette A1 (ABCA1) variant has been consistently associated with HDL-C levels, its association with diabetes and other metabolic parameters is unclear. Login to comment
5 Multivariate regression models were constructed to assess the interaction between the proportion of dietary macronutrients and the R230C polymorphism on metabolic parameters. Login to comment
11 Jacobo-Albavera et al. Nutrition & Metabolism (2015) 12:45 DOI 10.1186/s12986-015-0040-3 (Continued from previous page) Conclusion: This is the first study reporting a gender-specific interaction between ABCA1/R230C variant and dietary carbohydrate and fat percentages affecting VAT/SAT ratio, GGT, ALP, adiponectin levels and HOMA index. Our study confirmed the previously reported gender-specific ABCA1-diet interaction affecting HDL-C levels observed in an independent study. Our results show how gene-environment interactions may help further understand how certain gene variants confer metabolic risk, and may provide information useful to design diet intervention studies. Login to comment
12 Keywords: ABCA1, R230C, Gene-diet interaction, Insulin resistance, Adiponectin, Visceral to subcutaneous abdominal fat ratio, GGT, HDL-C Background The ATP-binding cassette A-1 protein (ABCA1) is essential for the transport of lipids across plasma membranes and cholesterol homeostasis, is known to have various functions in distinct tissues and plays an essential role in metabolism [1]. Login to comment
26 Significant interactions of ABCA1 gene variants with dietary macronutrients affecting plasma lipid levels have been reported in the Inuit population [36], in healthy young Chinese individuals [37] and in Mexican premenopausal women [38], and two diet intervention studies reported significantly different responses in BMI, HDL-C and serum adiponectin levels in individuals bearing the ABCA1/R230C variant [39, 40]. Login to comment
27 The ABCA1/R230C variant (rs9282541) was found to be private to the Americas and strongly associated with low HDL-C in Mexican mestizos and Native American populations [15, 41]. Login to comment
29 Although the ABCA1/R230C variant has been consistently associated with HDL-C levels, its association with diabetes and other metabolic parameters is unclear. Login to comment
30 Thus, we aimed to explore whether gender, menopausal status and dietary macronutrient composition modulate the effect of the ABCA1/R230C variant on plasma lipid levels and other cardiometabolic risk parameters. Methods The study included a total of 1598 controls recruited from the GEA Study, which was designed to investigate genetic factors associated with premature coronary artery disease, subclinical atherosclerosis and other coronary risk factors in the Mexican population [21]. Login to comment
41 The ABCA1/R230C variant (rs9282541) was genotyped using TaqMan assay number C_11720861_10, following the manufacturer`s recommendations in an ABI Prism 7900HT sequence detection system (Applied Biosystems). Login to comment
48 Pearson`s correlations were calculated to study the linear relationship between macronutrient proportions and anthropometric and metabolic variables, stratified by gender, menopausal status and ABCA1/R230C genotype. Login to comment
51 Multivariate regression models were used to assess the interaction between the proportion of dietary components and the R230C variant on the dependent variables and to assess their predictive effect, adjusting for age, BMI and alcohol consumption as appropriate. Login to comment
52 The study power to detect interactions between the ABCA1/R230C variant and dietary fat percentage affecting HDL-C, HOMA-IR, VAT/SAT ratio, adiponectin, ALP and GGT levels in premenopausal women was calculated using QUANTO software version 1.2.4 [50], assuming a dominant model with a minor allele (T) frequency of 0.11 and parameters estimated from the study population. Login to comment
54 Results Anthropometric and biochemical characteristics of the population stratified according to gender and menopausal status are shown in Additional file 1: Tables S1 and S2. All correlations between macronutrient percentages and metabolic parameters stratified by gender, menopausal status and ABCA1/R230C genotypes are depicted as a correlation matrix in Fig. 1. Login to comment
58 Median values for these six metabolic parameters according to ABCA1/ R230C genotypes in the entire study population and in premenopausal women are described in Additional file 1: Table S4. Additional file 1: Tables S5 and S6 show median values for these metabolic parameters according to genotype and stratified by dietary carbohydrate and fat percentage tertiles. Login to comment
60 Both carbohydrate and fat ABCA1/R230C interactions affecting HDL-C and adiponectin serum levels showed statistical significance (Pinteraction <0.04) (Figs. 2a and 3a). Login to comment
63 Interactions between ABCA1/R230C and dietary carbohydrate and fat affecting VAT/SAT ratio, ALP and GGT levels were statistically significant (P < 0.03) (Figs. 2c, 3b and 3c); these interactions showed a tendency to significance for HOMA-IR (P = 0.075 and P = 0.058, respectively) (Fig. 2b). Login to comment
67 Discussion We present here evidence suggesting that dietary macronutrient proportions modulate the effect of the functional ABCA1/R230C gene variant on several metabolic parameters in premenopausal women. Login to comment
68 Although the total number of premenopausal women was small (n = 363), Fig. 1 Correlations between macronutrient percentages and metabolic parameters stratified by gender, menopausal status and ABCA1/R230C genotypes. Login to comment
72 All interactions indicate a metabolically unfavorable pattern in premenopausal women carrying the risk allele consuming higher carbohydrate and lower fat diets (lower HDL-C and adiponectin levels, higher VAT/SAT ratio, HOMA-IR and higher GGT and % Dietary Carbohydrate log(HDL-C) 1.50 1.55 1.60 1.65 1.70 1.75 1.80 30 35 40 45 50 55 60 65 70 RR 30 35 40 45 50 55 60 65 70 RC/CC % Dietary Fat log(HDL-C) 1.45 1.50 1.55 1.60 1.65 1.70 1.75 1.80 15 20 25 30 35 40 45 50 RR 15 20 25 30 35 40 45 50 RC/CC % Dietary Carbohydrate log(HOMA-IR) 0.3 0.4 0.5 0.6 0.7 0.8 30 35 40 45 50 55 60 65 70 RR 30 35 40 45 50 55 60 65 70 RC/CC % Dietary Fat log(VAT/SAT) -0.6 -0.5 -0.4 -0.3 -0.2 15 20 25 30 35 40 45 50 RR 15 20 25 30 35 40 45 50 RC/CC % Dietary Fat log(HOMA-IR) 0.4 0.5 0.6 0.7 0.8 15 20 25 30 35 40 45 50 RR 15 20 25 30 35 40 45 50 RC/CC % Dietary Carbohydrate log(VAT/SAT) -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 30 35 40 45 50 55 60 65 70 RR 30 35 40 45 50 55 60 65 70 RC/CC Pinteraction = 0.035 Pinteraction = 0.031 Pinteraction = 0.075 Pinteraction = 0.058 Pinteraction = 0.003 Pinteraction = 0.003 A B C Fig. 2 ABCA1/R230C-Dietary Macronutrient Interactions Affecting HDL-C Levels, HOMA-IR and VAT/SAT Ratio in Premenopausal Women. Legend: Predicted values for: a HDL-C serum levels, b HOMA-IR and c VAT/SAT ratio in premenopausal women according to the percentage of dietary carbohydrate and fat intake, stratified by ABCA1/R230C genotypes under a dominant model (RR = wildtype homozygotes and RC/CC = risk allele heterozygotes and homozygotes) ALP levels); and a more favorable metabolic pattern in premenopausal women carrying the risk allele with higher fat and lower carbohydrate diets (higher HDL-C and adiponectin levels, and lower VAT/SAT ratio, HOMA-IR, GGT and ALP levels). Login to comment
73 Gender differences in carbohydrate and fat metabolism are well known [51, 52] and gender % Dietary Fat log(GGT) 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 15 20 25 30 35 40 45 50 RR 15 20 25 30 35 40 45 50 RC/CC % Dietary Carbohydrate log(GGT) 1.0 1.1 1.2 1.3 1.4 1.5 1.6 30 35 40 45 50 55 60 65 70 RR 30 35 40 45 50 55 60 65 70 RC/CC % Dietary Fat log(ALP) 1.70 1.75 1.80 1.85 1.90 1.95 2.00 2.05 15 20 25 30 35 40 45 50 RR 15 20 25 30 35 40 45 50 RC/CC % Dietary Carbohydrate log(ALP) 1.70 1.75 1.80 1.85 1.90 1.95 2.00 30 35 40 45 50 55 60 65 70 RR 30 35 40 45 50 55 60 65 70 RC/CC % Dietary Carbohydrate log(Adiponectin) 0.7 0.8 0.9 1.0 1.1 1.2 1.3 30 35 40 45 50 55 60 65 70 RR 30 35 40 45 50 55 60 65 70 RC/CC Pinteraction = 0.026 Pinteraction = 0.020 Pinteraction = 0.007 Pinteraction = 0.021 Pinteraction = 0.014 Pinteraction = 0.005 % Dietary Fat log(Adiponectin) 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 15 20 25 30 35 40 45 50 RR 15 20 25 30 35 40 45 50 RC/CC A B C Fig. 3 ABCA1/R230C-Dietary Macronutrient Interactions Affecting Adiponectin, ALP and GGT Levels in Premenopausal Women. Legend: Predicted values for: a serum adiponectin, b ALP and c GGT levels in premenopausal women according to the percentage of dietary carbohydrate and fat intake, stratified by ABCA1/R230C genotypes under a dominant model (RR = wildtype homozygotes and RC/CC = risk allele heterozygotes and homozygotes) differences in metabolic changes in response to diet have been previously published [53-57], mostly evident in women of reproductive age. Login to comment
75 In the GEA control group, ABCA1/R230C was significantly associated with HDL-C levels [21], but not with any other metabolic variable. Login to comment
81 However, in agreement with the report of Romero-Hidalgo et al. in an independent Mexican population [38], this inverse correlation was significantly higher in premenopausal women bearing the ABCA1/R230C allele (Pinteraction = 0.04). Login to comment
82 Also in agreement with this observation, hyperlipidemic R230C allele carriers showed a better HDL-C serum concentration response when fed a low-saturated fat diet supplemented with 25 g soy protein and 15 g soluble fiber, and this response was more evident in women [39], although the total proportion of macronutrients of this diet was not indicated. Login to comment
83 Thus, three independent studies, two based on food frequency questionnaires and one diet intervention study, confirm a gender-specific ABCA1/R230C-diet interaction affecting HDL-C serum levels. Login to comment
85 To our knowledge, the R230C variant was significantly associated with lower TG and total cholesterol levels in Mayans and Pimas from the United States in only one study [41], and the authors suggested that other genetic or environmental factors may play a role on the effect of ABCA1 on these and other metabolic traits. Login to comment
88 Because ABCA1/230C allele is less frequent than the ABCA1/219K allele, a greater sample size may be necessary to uncover a possible R230C-macronutrient interaction affecting TG levels. Login to comment
102 The ABCA1/R230C variant was associated with early-onset T2D in two independent small cohorts of the Mexican population [20], was only marginally associated with T2D in Pimas (P = 0.06) [41], and was not associated T2D in a case-control study of the Colombian population [23]. Login to comment
104 In the present study, it was not possible to directly assess R230C-diet interactions affecting T2D susceptibility because of the low number of premenopausal women with T2D (n = 29). Login to comment
105 However, interactions affecting T2D-associated metabolic risk parameters (HOMA-IR, VAT/SAT ratio and adiponectin levels) showed the same unfavorable pattern in premenopausal women bearing R230C genotypes with high dietary carbohydrate intake (Figs. 2b, 2c and 3a). Login to comment
108 Although the ABCA1/ R230C diet interactions affecting HOMA-IR observed here had marginal significance (Pinteraction = 0.058 and 0.075 for dietary fat and carbohydrate intake respectively), our data suggest that gender and diet are factors that added to ABCA1 function participate in the complex process of insulin resistance, and deserve further study. Login to comment
112 Moreover, although ABCA1 has not been found to be associated with this trait in GWAS or candidate gene association studies, a dietary intervention study including nopal, chia seed, soy protein and oat reported that individuals with metabolic syndrome bearing the ABCA1/R230C variant responded with a greater decrease in body weight and a sharper increase in serum adiponectin concentrations [40]. Login to comment
113 Thus, the significant interactions between the ABCA1/R230C variant and dietary fat/carbohydrate percentages observed in premenopausal women from the GEA study support this link between ABCA1 and serum adiponectin levels. Login to comment
114 Similarly, increased VAT/SAT ratio is associated with increased metabolic risk and T2D [71], and although ABCA1 has not been associated with VAT/SAT ratio, it was recently identified as a novel locus associated with body fat distribution with a stronger effect in women [22], and BMI was found to be positively associated with VAT/SAT ratio in premenopausal women from the GEA study bearing the ABCA1/R230C [21] . Login to comment
116 Interestingly, very significant interactions were observed affecting GGT and ALP serum levels, showing the same unfavorable pattern in premenopausal women bearing the R230C variant with higher dietary carbohydrate and lower dietary fat percentages. Login to comment
119 ABCA1 is expressed in gallbladder and plays a role in cholesterol concentrations in bile [76, 77], and thus higher ALP and GGT levels observed in premenopausal women bearing ABCA1/R230C and consuming high carbohydrates might be related to a higher risk of cholestasis or cholelithiasis. Login to comment
129 Conclusion To our knowledge, this is the first study reporting a gender-specific interaction between ABCA1/R230C variant and dietary carbohydrate and fat percentages affecting VAT/SAT ratio, GGT, ALP and adiponectin levels and HOMA index. Our study also replicated previously reported ABCA1-diet interaction affecting HDL-C levels in Mexican premenopausal women observed in an independent study. Our results show how gene-environment interactions may help further understand how certain gene variants confer metabolic risk, and may provide information useful to design diet intervention studies. Login to comment
135 Correlation between metabolic parameters and dietary macronutrients according to ABCA1/ R230C genotypes in premenopausal women. Table S4. Login to comment
136 Comparison of biochemical parameters stratified by ABCA1/R230C genotypes in the study population and premenopausal women. Table 5. Login to comment
137 Comparison of biochemical parameters stratified by ABCA1/R230C genotypes and carbohydrate percentage tertiles in premenopausal women. Table 6. Login to comment
138 Comparison of biochemical parameters stratified by ABCA1/R230C genotypes and fat percentage tertiles in premenopausal women. Login to comment
205 Villarreal-Molina MT, Aguilar-Salinas CA, Rodriguez-Cruz M, Riano D, Villalobos-Comparan M, Coral-Vazquez R, et al. The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. Login to comment
225 Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, et al. Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population. Diabetes. Login to comment
228 Villarreal-Molina T, Posadas-Romero C, Romero-Hidalgo S, Antunez-Arguelles E, Bautista-Grande A, Vargas-Alarcon G, et al. The ABCA1 gene R230C variant is associated with decreased risk of premature coronary artery disease: the genetics of atherosclerotic disease (GEA) study. Login to comment
294 Romero-Hidalgo S, Villarreal-Molina T, Gonzalez-Barrios JA, Canizales-Quinteros S, Rodriguez-Arellano ME, Yanez-Velazco LB, et al. Carbohydrate intake modulates the effect of the ABCA1-R230C variant on HDL cholesterol concentrations in premenopausal women. Login to comment