ABCMdb

PMID: 17287470

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., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. Login to comment 35 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys R230C variant genotyping. Login to comment 78 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys The relationship of the R230C variant with anthropometric and biochemical measurements is shown in Table 2. Login to comment 103 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys *P value comparing R230C/C230C vs. R230R. Login to comment 122 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys *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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Thus, the high frequency of R230C in Mexicans may be responsible for this modest peak. Login to comment 146 ABCA1 p.Arg230Cys R230C does not seem to abolish cholesterol efflux in HDL-forming cells, but it could be a functional variant. Login to comment 148 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys The association of R230C with BMI in Mexican Mestizos was more significant than that observed for lowering HDL cholesterol levels. Login to comment 159 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Further studies are required to understand the role of ABCA1 and the R230C variant in adipocytes. Login to comment 167 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys We also found a significant association of R230C with type 2 diabetes in the Mexican-Mestizo population. Login to comment 178 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys High prevalence of R230C in Amerindian populations. Login to comment 185 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Interestingly, R230C seems to be found exclusively in Amerindian and Amerindian-derived populations such as Mexican Mestizos. Login to comment 190 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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