eplication of genome wide association-validated loci for type 2 diabetes mellitus in the Saudi Arabian population

Abstract

Background: Previous genome wide association studies in Caucasian and South Asian populations have identified over 35 loci for Type 2 Diabetes Mellitus (T2DM) risk. However, little is known about the contribution of these loci in T2DM from a Saudi Arabian population. In this study we investigated for the first time, the association of 38 previously identified T2DM risk loci (32 loci from Caucasian and 6 loci from South Asian populations) in 1,166 T2DM patients and 1,235 healthy controls from Saudi Arabia. Methods: All DNA samples from cases and controls were genotyped for 38 SNPs using the KASPar method (KBioscience, Hoddesdon UK). Results: Common genetic variants (in or near WFS1, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, HNF4A, and DUSP9) showed significant (P< 0.05) associations with T2DM in our study population. The effect sizes of these loci were comparable to those previously identified with the exception of HNF4A which showed evidence of heterogeneity with a trend for larger effect size in our study population (OR, 95% CI; 1.27, 1.07-1.51) compared to that reported in South Asian populations (1.09, 1.06-1.12, I2 = 65.9). Analysis of risk allele scores (RAS) defined by the T2DM-associated loci showed that subjects in the top 20% of the RAS distribution (n = 480) had 2.5 fold increase in disease risk as compared to those in the lower 20% (n = 480; P = 9.5 x 10-12). RAS were also associated with fasting glucose level (β = 0.12; P = 2.2 x 10-9) but not with BMI (P = 0.19). Conclusion: In conclusion we have shown for the first time that variants at WFS1, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, HNF4A, and DUSP9 are associated with T2DM in the Saudi population but further larger studies will be required to confirm these findings in other Middle Eastern populations with high T2DM prevalence and to identify other T2DM-susceptibility loci.