Abstract
In our attempt to comprehensively understand the nature of association of variants at 11q23.3 apolipoprotein gene cluster region, we genotyped a prioritized set of 96 informative SNPs using Fluidigm customized SNP genotyping platform in a sample of 508 coronary artery disease (CAD) cases and 516 controls. We found 12 SNPs as significantly associated with CAD at P <0.05, albeit only four (rs2849165, rs17440396, rs6589566 and rs633389) of these remained significant after Benjamin Hochberg correction. Of the four, while rs6589566 confers risk to CAD, the other three SNPs reduce risk for the disease. Interaction of variants that belong to regulatory genes BUD13 and ZPR1 with APOA5-APOA4 intergenic variants is also observed to significantly increase the risk towards CAD. Further, ROC analysis of the risk scores of the 12 significant SNPs suggests that our study has substantial power to confer these genetic variants as predictors of risk for CAD, as illustrated by AUC (0.763; 95% CI: 0.729–0.798, p = <0.0001). On the other hand, the protective SNPs of CAD are associated with elevated Low Density Lipoprotein Cholesterol and Total Cholesterol levels, hence with dyslipidemia, in our sample of controls, which may suggest distinct effects of the variants at 11q23.3 chromosomal region towards CAD and dyslipidemia. It may be necessary to replicate these findings in the independent and ethnically heterogeneous Indian samples in order to establish this as an Indian pattern. However, only functional analysis of the significant variants identified in our study can provide more precise understanding of the mechanisms involved in the contrasting nature of their effects in manifesting dyslipidemia and CAD.
Highlights
Coronary artery disease (CAD) is most predominant and ranks as number one in causing deaths due to cardiovascular diseases (CVDs) in India
It is apparent from the candidate gene association studies that relatively greater number of lipoprotein metabolism related genes is observed to be more consistently associated with CAD as compared to the candidate genes related to other metabolisms [3]
A GWAS conducted on a sample of glycemic and non glycemic subjects, as part of Sikh Diabetes Study (SDS),Sanghera et al [8] observed an intronic variant of ZPR1 regulatory gene rs12286037 to be associated with triglycerides
Summary
Coronary artery disease (CAD) is most predominant and ranks as number one in causing deaths due to cardiovascular diseases (CVDs) in India. The primary event of atherosclerosis is the endothelial injury or dysfunction, which is triggered by abnormal lipoprotein metabolism with subsequent dyslipidemia [2]. It is apparent from the candidate gene association studies that relatively greater number of lipoprotein metabolism related genes is observed to be more consistently associated with CAD as compared to the candidate genes related to other metabolisms [3]. Among the genes that regulate this metabolism, apolipoprotein genes that code for cofactors of several enzymes of cholesterol transport system are the key regulators These genes are primarily found as clusters on chromosome 11 and 19. Exclusive attempts were made to comprehensively understand the role of genetic variants in this lipid influencing region among the Caucasians [10] and north Indian Punjabis [8] and a couple of polymorphisms were found to be associated with high density lipoprotein cholesterol (HDL-C) and plasma triglyceride (TG) concentrations
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