Back ground and Aims: Conventional risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of coronary artery disease (CAD) risk prediction algorithms, but provide only modest discrimination. A genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors alone. The current study analysed the genetic risk of CAD in Pakistani subjects using a GRS of 21 loci in 18 genes and examined whether its association with blood lipids in this cohort.Methods: 625 subjects were genotyped for the variants, NOS3 rs1799983, SMAD3 rs17228212, APOBrs1042031, LPArs3798220, LPA rs10455872, SORT1rs646776, APOE rs429358, GLUL rs10911021 and FTO rs9939609 (by TaqMan) and MIA3 rs17465637,CDKN2A rs10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328,LPL rs1801177, PCSK9 rs11591147and APOE rs7412 (by KASPar technique).Results: Individually, risk allele frequencies were not significantly higher in cases than controls (p>0.05) except for APOB rs1042031 and FTO rs9939609 (p=0.007 and 0.003 respectively), and did not associate with CAD except rs1042031 and rs993969 (p=0.01 and 0.009 respectively). However, the GRS of 21 SNPs was significantly higher in cases than controls (17.53±2.52 vs16.64±2.44, p<0.001) and was associated with CAD risk. CAD risk in the top quintile of GRS was 2.96 (95% CI 1.71-5.13). Atherogenic blood lipid levels showed significant positive association with GRS.
Conclusion:The GRS was quantitatively associated with d CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be in part at least through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.