By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells.
However, for these SNPs, only modest associations were found with a higher incidence of T2D: hazard ratios of 2.03 [1.00-4.11] for MMP26 (rs2499953 P = 0.05) and 1.33 [1.02-1.73] for NGN3 (rs10823406 P = 0.03).
Polymorphisms of these genes (Ala45Thr [NEUROD1], Ser199Phe [NEUROG3], and Ala98Val [TCF1]) have been postulated to influence the development of type 2 diabetes.
Mutations and polymorphisms of ngn3 gene are not significantly associated with Type II (non-insulin-dependent) diabetes mellitus in the Japanese subjects.