Genetic variants of FOXA2: risk of type 2 diabetes and effect on metabolic traits in North Indians

Here, we examined the association of genetic variants of FOXA2, an upstream activator of the beta-cell transcription factor network, with type 2 diabetes and related phenotypes in North India. We genotyped three SNPs (rs1212275, rs1055080, rs6048205) and the (TCC) (n) repeat polymorphism in 1,656 participants comprising 1,031 patients with type 2 diabetes and 625 controls. SNPs rs1212275 and rs6048205 were uncommon (MAF < 5%) with similar distribution among patients and controls. We found a strong association of (TCC) (n) common allele A5 with type 2 diabetes [OR = 1.66 (95% CI 1.36-2.04, p = 5.9 x 10-7) for A5 homozygotes]. Obese individuals with A5A5 genotype had enhanced risk when segregated from normal-weight subjects [OR = 1.92 (95% CI 1.47-2.51), p = 1.6 x 10-6]. A5 was also nominally associated with higher fasting glucose (p = 0.02) and lower fasting insulin (p = 0.0028) and C-peptide (p = 0.036) levels among controls. At the rs1055080 locus, GG was found to provide reduced risk among normal-weight subjects [OR = 0.59 (95% CI 0.40-0.88), p = 0.011]. Combination of protective GG and non-risk genotypes of (TCC) (n) showed reduced risk of type 2 diabetes both among normal-weight [OR = 0.43 (95% CI 0.29-0.65), p = 1.2 x 10-6] and obese individuals [0.47 (95% CI 0.34-0.64), p = 4.3 x 10-5]. For the first time we demonstrated that FOXA2 variants may affect risk of type 2 diabetes and metabolic traits in North India, however replication analyses in other cohorts are required to confirm the findings.