ABCMdb

PMID: 26579206

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., [PubMed]

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0 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 87 ABCA1 p.Arg219Lys A larger study using food frequency questionnaires reported that high saturated fat intake was associated with higher triacylglycerol serum levels in Inuit individuals bearing the CC genotype of ABCA1/R219K (rs2230806), with no gender effect reported [36]. Login to comment 88 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Correlation between metabolic parameters and dietary macronutrients according to ABCA1/ R230C genotypes in premenopausal women. Table S4. Login to comment 136 ABCA1 p.Arg230Cys Comparison of biochemical parameters stratified by ABCA1/R230C genotypes in the study population and premenopausal women. Table 5. Login to comment 137 ABCA1 p.Arg230Cys Comparison of biochemical parameters stratified by ABCA1/R230C genotypes and carbohydrate percentage tertiles in premenopausal women. Table 6. Login to comment 138 ABCA1 p.Arg230Cys Comparison of biochemical parameters stratified by ABCA1/R230C genotypes and fat percentage tertiles in premenopausal women. Login to comment 205 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 291 ABCA1 p.Arg219Lys Liu H, Lin J, Zhu X, Li Y, Fan M, Zhang R, et al. 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. Login to comment 294 ABCA1 p.Arg230Cys 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