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, IGF2BP2, 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 β-cell function (β-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 × 10^-21). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (b = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = 20.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = 20.032, SE = 0.0140, P = 0.022), and C-peptide index (β = 20.031, SE = 0.012, P = 0.0125). CONCLUSIONS - Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell-preserving therapy.