Translational Biomedicine

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Pilot Genome wide Linkage Analysis in Asian Indian Families with Coronary Artery Disease

Jayashree Shanker

Background and Objectives: Asian Indians show an inherent predisposition to premature Coronary Artery Disease (CAD) with a strong family history and therefore serve as a suitable population for identifying novel genes linked to CAD. We performed pilot linkage analysis on a subset of Asian Indian families selected from the Indian Atherosclerosis Research Study (IARS) to identify putative loci linked to CAD.

Methods & Findings: We performed linkage study on six multiplex families consisting of 31 affected sibling pairs (ASPs). Families were ascertained through the proband who had angiographically confirmed CAD, with age at onset < 60 years for males and <65 years for females. Linkage mapping set v 2.5-MD10, comprising of 400 fluorescent labeled microsatellite markers were genotyped in 31 ASPs. Quantitative trait loci (QTL) analysis was carried out for sixteen atherothrombotic biomarkers and non parametric linkage analysis was performed by affected sib-pair method.  There was suggestive evidence of linkage at 4q21.21, 6q22.33, 6q23, 6q24.2 and 8q24.1 to CAD (Logarithm of Odds – LOD score ≥  1; p<0.05). Bioinformatics analysis of significant linkage peaks identified key genes associated with inflammation and immune response. QTL analysis revealed suggestive evidence of linkage  to Xp22.3 locus for total cholesterol (LOD =1.7) and at various loci on chromosomes  1,2,4,11 and X for Fibrinogen, Interleukin 2, Apolipoprotein A1, High density lipoprotein cholesterol and Apolipoprotein B (LOD >1; p<0.05), respectively.

Conclusion: Novel loci on chromosome 4,6 and 8 has shown suggestive evidence of linkage to CAD; their role in the etio-pathogenesis of CAD remains to be established.