Genetic Risk Score Constructed Using 14 Susceptibility Alleles for Type 2 Diabetes Is Associated With the Early Onset of Diabetes and May Predict the Future Requirement of Insulin Injections Among Japanese Individuals

OBJECTIVE-We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes. RESEARCH DESIGN AND METHODS-We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, 1GF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to beta-cell function (beta-GRS) and then assessing the association between each GRS and the clinical features. RESULTS-Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 x 10(-21)). Among the subjects with type 2 diabetes, the beta-GRS was associated with individuals receiving insulin therapy (beta = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (beta = -0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (beta = -0.032, SE = 0.0140, P = 0.022), and C-peptide index (beta = -0.031, SE = 0.012, P = 0.0125). CONCLUSIONS-Our data suggest that the beta-GRS is associated with reduced beta-cell functions and may be useful for selecting patients who should receive more aggressive beta-cell preserving therapy.