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

Minoru Iwata, Shiro Maeda, Yutaka Kamura, Atsuko Takano, Hiromi Kato, Shihou Murakami, Kiyohiro Higuchi, Atsushi Takahashi, Hayato Fujita, Kazuo Hara, Takashi Kadowaki, Kazuyuki Tobe, Minoru Iwata, Shiro Maeda, Yutaka Kamura, Atsuko Takano, Hiromi Kato, Shihou Murakami, Kiyohiro Higuchi, Atsushi Takahashi, Hayato Fujita, Kazuo Hara, Takashi Kadowaki, Kazuyuki Tobe

Abstract

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 (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = -0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = -0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = -0.031, 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.

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