Distinct Patterns of Association of Variants at 11q23.3 Chromosomal Region with Coronary Artery Disease and Dyslipidemia in the Population of Andhra Pradesh, India

<div><p>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 <i>BUD13</i> and <i>ZPR1</i> with <i>APOA5</i>-<i>APOA4</i> 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.</p></div

Summary results of best SNP-SNP interaction model using GMDR.

<p>Summary results of best SNP-SNP interaction model using GMDR.</p

Allelic association of variants at 11q23.3 chromosomal region with CAD along with chi-square values and odds ratios from logistic regression, before and after adjusting for covariates- age, sex and quantitative lipid traits.

<p>Allelic association of variants at 11q23.3 chromosomal region with CAD along with chi-square values and odds ratios from logistic regression, before and after adjusting for covariates- age, sex and quantitative lipid traits.</p

Plot of odds ratios according to risk categories

<p>Plot of odds ratios according to risk categories</p

Percentage of CAD cases and controls with cumulative risk scores for CAD associated variants and results of logistic regression analysis of risk categories on CAD.

<p>Percentage of CAD cases and controls with cumulative risk scores for CAD associated variants and results of logistic regression analysis of risk categories on CAD.</p

Significant SNP-SNP interaction effects on CAD obtained through pair wise logistic regression.

<p>Significant SNP-SNP interaction effects on CAD obtained through pair wise logistic regression.</p

Relative proportion of cases and controls in the 12 risk categories

<p>Relative proportion of cases and controls in the 12 risk categories</p

Details of haplotype blocks at 11q23.3 chromosomal region with their SNPs.

<p>Details of haplotype blocks at 11q23.3 chromosomal region with their SNPs.</p

Linkage Disequilibrium plot of SNPs at 11q23.3 chromosomal region encompassing BUD13-ZPR1, APOA1-C3-A4-A5 genes.

<p>Pair wise LD among 63 SNPs is indicated by diamonds shaded in white–pink–red, the strength of LD reflected in the intensity of colour, from D’ = 0 in white to D’ = 1 in red. The 11 blocks represent the presence of strong LD. </p

Haplotype association of variants at 11q23.3 chromosomal region with CAD, chi-square values and odds ratios from logistic regression analysis before and after adjusting for age and sex.

<p>Haplotype association of variants at 11q23.3 chromosomal region with CAD, chi-square values and odds ratios from logistic regression analysis before and after adjusting for age and sex.</p