ABCMdb

PMID: 23152888

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., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036). Login to comment 7 ABCA1 p.Arg230Cys Conclusion: This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. Login to comment 8 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys The ABCA1/R230C variant (rs9282541) was genotyped using TaqMan assays (ABI Prism 7900HT sequence detection system (Applied Biosystems). Login to comment 58 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys No significant BMI-R230C interactions were observed for LSAR (data not shown). Login to comment 85 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Association of the R230C/ABCA1 variant with premature coronary artery disease and subclinical artherosclerosis. Login to comment 98 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Association of the R230C/ABCA1 variant with quantitative metabolic parameters. Login to comment 113 ABCA1 p.Arg230Cys Associations of the R230C/ABCA1 variant with metabolic risk factors for coronary artery disease. Login to comment 128 ABCA1 p.Arg230Cys 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 132 ABCA1 p.Val825Ile In this regard, heterozygosity for loss of function ABCA1 mutations were associated with lower plasma HDL-cholesterol levels, but not with an increased risk of ischemic heart disease after adjusting for known cardiovascular risk factors [10]; ABCA1 variants V772M and V825I were both associated with increased HDL-C levels and increased IHD risk [12], and the ABCA1 promoter variant rs2422498 was associated with a decreased risk of 10-year vascular death in CAD patients with no apparent effect on HDL-C levels [33]. Login to comment 133 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys The BMI-R230C interactions observed only in pre-menopausal women suggest that these effects may be estrogen-related. Login to comment 149 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys Conclusion This is the first study assessing the effect of the R230C/ABCA1 variant in premature coronary artery disease. Login to comment 161 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys 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 ABCA1 p.Arg230Cys (TIF) Figure S2 The interaction of R230C and BMI affects triglyceride levels in women. Lines represent simple linear regressions. Login to comment 171 ABCA1 p.Arg230Cys 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