1. 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 Featured Article: Minoru Iwata, M.D., Ph.D., Shiro Maeda, M.D., Ph.D., Yutaka Kamura, M.D., Atsuko Takano, M.D., Ph.D., Hiromi Kato, M.D., Ph.D., Shihou Murakami, M.D., Ph.D., Kiyohiro Higuchi, M.D., Ph.D., Atsushi Takahashi, Ph.D.,Hayato Fujita, M.D., Kazuo Hara, M.D., Ph.D., Takashi Kadowaki, M.D., Ph.D., Kazuyuki Tobe, M.D., Ph.D. Diabetes Care Volume 35: 1763-1770 August, 2012

2. Study Objective To evaluate the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes Iwata M et al. Diabetes Care 2012;35:1763-1770

3. Study Design Analyzed 14 SNPs in 1487 Japanese individuals (724 with type 2 diabetes and 763 controls): HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, C2CD4A/B GRS calculated according to the number of risk alleles by counting: All 14 SNPs (T-GRS) 11 SNPs related to b-cell function (β-GRS) Assessed association between each GRS and clinical features Iwata M et al. Diabetes Care 2012;35:1763-1770

4. Results 4 SNPs significantly associated with type 2 diabetes in the sample (P = 0.0036) T-GRS significantly associated with type 2 diabetes (P = 5.9 x 10 -21 ) Among subjects with type 2 diabetes, β-GRS associated with: Receiving insulin therapy (β = 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) C-peptide index (β = 20.031, SE = 0.012, P = 0.0125). Iwata M et al. Diabetes Care 2012;35:1763-1770

9. Conclusions β-GRS is associated with reduced β-cell function and may be useful for selecting patients who should receive more aggressive β-cell–preserving therapy Iwata M et al. Diabetes Care 2012;35:1763-1770