Assessing the clinical utility of the genetic information using the genotype data for GWAS-derived type 2 diabetes susceptibility variants in a Japanese population.

• Project/Area Number: 24510276
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical genome science
• Research Institution: University of Toyama
• Principal Investigator: IWATA MINORU 富山大学, 大学院医学薬学研究部(医学), 准教授 (20345565)
• Co-Investigator(Kenkyū-buntansha): TOBE Kazuyuki 富山大学, 大学院医学薬学研究部(医学), 教授 (30251242)
• Research Collaborator: HARA Kazuo 東京大学, 医学部附属病院糖尿病・代謝内科 (50359600) ; MAEDA Shiro 琉球大学大学院医学研究科, 先進ゲノム検査査医学講座・独立行政法人理化学研究所遺伝子多型研究センター (50314159) ; KAMURA Yutaka ; NAKAGAWA Hajime ; TAKANO Atsuko ; KATO Hiromi ; TEMARU Rie ; FUKUSHIMA Yasuo ; HIGUCHI Kiyohiro ; TAKI Kazuko ; IGARASHI Yasuhumi ; SAWASAKI Shigeki
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 疾患関連遺伝子 / ゲノム

Outline of Final Research Achievements

We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes(T2D). We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1487 Japanese individuals (724 patients with T2D and 763 controls). 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. The T-GRS was significantly associated with T2D (P = 5.9 × 10-21). Among the subjects with T2D, the β-GRS was associated with individuals receiving insulin therapy ( P = 0.0431), age at diagnosis (P = 0.0029), and C-peptide index (P = 0.0125).
Our data suggests that the β-GRS is associated with reduced beta cell functions and may be useful for selecting patients who should receive more aggressive β-cell preserving therapy.

Research Products

• [Journal Article] Replication study in a Japanese population to evaluate the association between 10 SNP loci, identified in European genome-wide association studies, and type 2 diabetes. (2015)
  • Author(s): Matsuba R,, Sakai K, Imamura M, Tanaka Y, Iwata M, Hiroshe H, Kaku K, Maegawa H, WatadaH, Tobe K, Kashiwagi A, Kawamori R, Maeda S.
  • Journal Title: Plos One Volume: 10 Issue: 5 Pages: e0126363-e0126363
  • DOI: 10.1371/journal.pone.0126363
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genome-wide association study identifies three novel loci for type 2 diabetes (2014)
  • Author(s): Hara K, Fujita H, Johnson TA, Yamauchi T, Yasuda K, Horikoshi M, Peng C, Hu C, Ma RC, Imamura M, et al
  • Journal Title: Hum Mol Genet Volume: 23 Issue: 1 Pages: 239-246
  • DOI: 10.1093/hmg/ddt399
  • Peer Reviewed / Open Access
• [Journal Article] Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population (2013)
  • Author(s): Sakai K, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S
  • Journal Title: PLoS One Volume: 8 Issue: 9 Pages: e76317-e76317
  • DOI: 10.1371/journal.pone.0076317
  • Peer Reviewed
• [Journal Article] Assessing the clinical utility of a genetic risk score constructed using 49 susceptibility alleles for type 2 diabetes in a Japanese population (2013)
  • Author(s): Imamura M, Shigemizu D, Tsunoda T, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi A, Kawamori R, Maeda S
  • Journal Title: J Clin Endocrinol Metab Volume: 98(10) Issue: 10 Pages: E1667-E1673
  • DOI: 10.1210/jc.2013-1642
  • Peer Reviewed
• [Journal Article] Replication study for the association of a single-nucleotide polymorphism, rs3746876, within KCNJ15, with susceptibility to type 2 diabetes in a Japanese population (2013)
  • Author(s): Fukuda H, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S.
  • Journal Title: J Hum Genet Volume: 58 Issue: 7 Pages: 490-493
  • DOI: 10.1038/jhg.2013.28
  • NAID: 10031190046
  • Peer Reviewed
• [Journal Article] Genome-wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India (2013)
  • Author(s): Saxena R, Yamauchi T, Hara K Saxena R, Yamauchi T, Hara K DIAGRAM MuTHER; TGEN, Kadowaki T
  • Journal Title: Diabetes Volume: 62 Issue: 5 Pages: 1746-1755
  • DOI: 10.2337/db12-1077
  • Peer Reviewed
• [Journal Article] Replication study for the association of rs391300 in SRR and rs17584499 in PTPRD with susceptibility to type 2 diabetes in a Japanese population (2013)
  • Author(s): Imamura M, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi A, Kadowaki T, Kawamori R and Maeda S
  • Journal Title: J Diabetes Invest Volume: Volume 4 Issue 2 Issue: 2 Pages: 168-173
  • DOI: 10.1111/jdi.12017
  • Peer Reviewed
• [Journal Article] 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 (2012)
  • Author(s): Iwata M, Hara K, Kadowaki T
  • Journal Title: Diabetes Care Volume: 35 Issue: 8 Pages: 1763-1770
  • DOI: 10.2337/dc11-2006
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population. (2012)
  • Author(s): Hisashi Fukuda
  • Journal Title: PLoS One Volume: 7 Issue: 9 Pages: e46263-e46263
  • DOI: 10.1371/journal.pone.0046263
  • Peer Reviewed
• [Journal Article] A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. (2012)
  • Author(s): Imamura M, Maeda S, Yamauchi T, Hara K, Yasuda K,..., Okada-Iwabu M, Iwabu M, Shojima N,..., Nakamura Y, Kadowaki T
  • Journal Title: Human Molecular Genetics Volume: 21 Issue: 13 Pages: 3042-3049
  • DOI: 10.1093/hmg/dds113
  • Peer Reviewed
• [Journal Article] Variations with modest effects have an important role in the genetic background of type 2 diabetes and diabetes-related traits (2012)
  • Author(s): Fujita H, Hara K, Kadowaki T
  • Journal Title: J Hum Genet Volume: 57 Issue: 12 Pages: 776-779
  • DOI: 10.1038/jhg.2012.110
  • NAID: 10031145885
  • Peer Reviewed
• [Presentation] 欧米人集団ゲノムワイド関連解析で同定された2型糖尿病感受性遺伝子領域の日本人集団における検証 (2014)
  • Author(s): 酒井 健輔, 今村 美菜子, 岩田 実, 広瀬 寛, 綿田 裕孝, 前川 聡, 戸辺 一之, 柏木 厚典, 加来 浩平, 河盛 隆造, 田中 逸, 前田 士郎
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] Type 2 diabetes genetic risk score is more strongly associated with basal insulin secretion and insulin requirement than family history in Japanese type 2 diabetic patients. (2013)
  • Author(s): Iwata M., Maeda S., Kamura Y., Takano A., Kato H., Murakami S., Higuchi K., Temaru R., Oda H., Asamizu S., Fukushima Y., Fukuda K., Yamazaki K., Usui ., and Tobe K.
  • Organizer: 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes
  • Place of Presentation: Barcelona
• [Presentation] Comparison of clinical usefulness between type 2 diabetes genetic risk score and family history in Japanese type 2 diabetic patients. (2013)
  • Author(s): Iwata M., Maeda S., Kamura Y., Takano A., Kato H., Murakami S., Higuchi K., Temaru R., Asamizu S., Oda H., Fukushima Y., and Tobe K.
  • Organizer: 14th International Diabetes Federation
  • Place of Presentation: Melbourne
• [Presentation] Genetic risk scoreと糖尿病家族歴の情報から成るfamily history scoreの糖尿病臨床像との関連性における比較検討 (2013)
  • Author(s): 岩田 実，前田士郎，加村 裕，高野敦子，村上史峰，加藤弘巳，福島泰男，手丸理恵，赤川直次，樋口清博，薄井 勲，石木 学，小橋親晃，山崎勝也，浦風雅春，浅水幸恵，井窪万里子，小田寛文，五十嵐保文，多喜和子，福田一仁，戸辺一之
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] FTO遺伝子多型は男性において糖尿病発症に関連する． (2012)
  • Author(s): 岩田 実，前田士郎，加村 裕，高野敦子，村上史峰，加藤弘巳，福島泰男，手丸理恵，赤川直次，樋口清博，他
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
• [Presentation] 遺伝的リスクスコア(Genetic risk score)は糖尿病診断時年齢やインスリン分泌能と関連する (2012)
  • Author(s): 岩田 実,前田 士郎, 加村 裕, 高野 敦子, 手丸 理恵, 加藤 弘巳, 赤川 直次, 村上 史峰, 樋口 清博, 戸辺 一之
  • Organizer: 第109回日本内科学会総会
  • Place of Presentation: 京都