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

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.

The SNP rs7865618 of 9p21.3 locus emerges as the most promising marker of coronary artery disease in the southern Indian population

“…Interestingly, the SNP included from 9p21.3 region in all the three combinations was found to be rs7865618. None of these three SNPs at 11q23.3 locus showed significant allelic association with CAD in the earlier study, except for the protective effect of rs2849165 11 . Nevertheless, in the pair wise SNP interaction analysis, all the three were shown to be contributing significantly to CAD risk in conjunction with rs7865618 from the 9p21.3 region.…”

“…However, the protective effect of the SNP in interaction with other SNPs of the same 9p21.3 region indicated that it may contribute to CAD risk through its interactions with variants at other loci. Given the significant effect of variants in 11q23.3 region on CAD pathology, we made an attempt to explore the nature of pair wise interactions between the 35 SNPs of 9p21.3 and 95 SNPs of 11q23.3, analysed by us in the previous study 11 , 12 . The results revealed three significant SNP-SNP combinations between these two chromosomal loci (Table 6 ), each pair represented one SNP from 11q23.3 locus (rs2187126 in the intron of BUD13, rs1263163 and rs2849165 both in the intergenic region of APOA5-APOA4 genes).…”

“…With its evolutionarily conserved function of forming pre m-RNA Retention and Splicing (RES) complex, BUD13 appears to be one of the key regulating genes of 11q23.3 region. Further, the APOA4-APOA5 genes are well known for their role in coding activating enzymes of cholesterol metabolism there by regulating cholesterol homeostasis 11 . It may be hypothesized from the findings of the present study that the variants in 11q23.3 chromosomal region harbouring apolipoprotein encoding or regulating genes might be involved in defective cholesterol homeostasis thereby resulting in increased levels of oxidised low density lipoproteins (LDLs).…”

“…All the cases were evaluated by interventional cardiologists at the CARE Hospitals, Hyderabad, for the above mentioned criteria. The baseline characteristics of CAD patients recruited for the present study were already furnished in the previous paper 11 .…”

“…There is an increase in prevalence of CAD in India, which could be attributed to their characteristic low High Density Lipoproteins (HDLs) and elevated triglycerides, termed as atherogenic dyslipidaemia 7 , 8 . Given this, we have recently investigated the pattern of association of 95 prioritized SNPs of the GWAS identified SNPs in the 11q23.3 region 9 , 10 in the CAD patients from Hyderabad, India 11 , 12 and observed significant association of 12 SNPs in the intronic regions of APOA1, BUD13, ZPR1 and the intergenic region of APOA5-APOA4 genes with distinct effects towards CAD and dyslipidemia. These studies also provided insights into the nature of association of these variants with different clinical and phenotypic categories of CAD suggesting complex nature of interactions between the variants in contributing to the clinical and phenotypic heterogeneity of CAD.…”