Genetic Markers of Lipids in Indians: A Validation Study of Most Relevant Findings of Genome-Wide Association Studies

We aimed to validate the GWAS loci (identified in European populations) related to serum lipid levels (total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C)) in the Indian population originally recruited to examine the 20-year trend of cardiometabolic risk factors in rural and urban areas around National Capital region in India. Isolated DNA was processed for genotyping of 12 established GWAS variants using multiplex Sequenom Mass ARRAY technology. We examined the association of these genetic variants with different lipid levels and found association of eight variants for lipid levels. We also derived weighted genetic risk scores (wGRAS) using the validated variants. The wGRS for triglycerides and VLDL-C was derived based on four associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, rs4420638 at APOC1) which was associated with 36.31 mg/dL elevated triglycerides and VLDL-C (β=0.95, SE=0.16, p<0.001). Similarly, every unit of combined risk score (rs2293889 at TRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL higher total cholesterol (β=1.01, SE=0.23, p<0.001) and 33.97 mg/dL higher LDL-C (β= 1.03, SE =0.19, p<0.001) based on its wGRS (rs2293889 at TRPS1, rs4147536 at ADH1B, rs4420638 at APOC1 and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 and FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1 and rs7832643 at PLEC) was associated with 10.64 mg/dL lower HDL-C (β= -0.87, SE =0.14, p<0.001). Therefore, we confirm the role of eight GWAS loci related to different lipid levels in the Indian population and demonstrate the combined effect of variants for lipid traits among Indians by deriving the weighted genetic risk scores.The phenotypic and genotypic data will be made available on the dbGaP portal for access. ]]>
Total 2117 samples (1220 urban and 897 rural particpants) were analyzed in this study. Urban participants were recruited from Municipal Corporation of Delhi, India and the rural participants were recruited from Ballabhgarh block of adjoining state of Haryana, India. For the present analyses, the blood samples were utilized for genotyping the selected variants related to lipid levels. The buffy coat samples of the particpants were processed for phenol-chloroform method of DNA isolation. The isolated DNA was then processed for genotyping of established GWAS SNPs using MASSARRAY iPLEX platform (former: Sequonome, current Agena Biosciences) that used multi-plex PCR technique for genotyping. These SNPs were slected based on their biological importance and high GWAS significance levels related to lipid traits. In this study, we report the effect sizes of the rs markers on the respective lipid trait.