Interaction between the UCP2-866G/A, mtDNA 10398G/A and PGC1alpha p.Thr394Thr and p.Gly482Ser polymorphisms in type 2 diabetes susceptibility in North Indian population.

In the recent past, we have observed a possible role of 10398A and 16189C mtDNA and PGC1alpha p.Thr394Thr (rs2970847) and p.Gly482Ser (rs8192673) variant genotypes providing susceptibility/protection against type 2 diabetes mellitus (T2DM) in two North Indian population groups. These initial observations encouraged us to look at the candidate genes in combination with -866G/A (rs659366) polymorphism in uncoupling protein 2 (UCP2) in a single study of a relatively large sample size, constituted of both the cohorts, to unravel an interesting outcome of an additive interaction in-between the studied genes. In a total of 1,686 individuals (762 cases and 924 controls) belonging to Indo-European linguistic group from North India, a comparison of risk genotype combinations of: UCP2-866GG, mtDNA 10398A and PGC1alpha p.Thr394Thr or p.Gly482Ser against the protective genotypes: UCP2-866XA, mtDNA 10398G and PGC1alpha p.Thr394Thr (nominal P value = 1.75 x 10(-14), Odds ratio, OR = 5.29, 3.40-8.22 at 95% CI) or PGC1alpha p.Gly482Ser (nominal p value = 4.42 x 10(-24), OR = 8.59, 5.53-13.35 at 95% CI), showed a highly significant difference and increased ORs. In a complex disease, it is always encouraging to find an additive interaction of multiple small effects of the studied candidate gene variations.