Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies

Yoshiji Yamada; Jun Sakuma; Ichiro Takeuchi; Yoshiki Yasukochi; Kimihiko Kato; Mitsutoshi Oguri; Tetsuo Fujimaki; Hideki Horibe; Masaaki Muramatsu; Motoji Sawabe; Yoshinori Fujiwara; Yu Taniguchi; Shuichi Obuchi; Hisashi Kawai; Shoji Shinkai; Seijiro Mori; Tomio Arai; Masashi Tanaka

doi:10.18632/oncotarget.19287

Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies

Oncotarget. 2017 Jul 17;8(46):80492-80505. doi: 10.18632/oncotarget.19287. eCollection 2017 Oct 6.

Authors

Yoshiji Yamada^{1

2}, Jun Sakuma^{2

3

4}, Ichiro Takeuchi^{2

4

5}, Yoshiki Yasukochi^{1

2}, Kimihiko Kato^{1

6}, Mitsutoshi Oguri^{1

7}, Tetsuo Fujimaki⁸, Hideki Horibe⁹, Masaaki Muramatsu¹⁰, Motoji Sawabe¹¹, Yoshinori Fujiwara¹², Yu Taniguchi¹², Shuichi Obuchi¹³, Hisashi Kawai¹³, Shoji Shinkai¹⁴, Seijiro Mori¹⁵, Tomio Arai¹⁶, Masashi Tanaka¹⁷

Affiliations

¹ Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.
² CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
³ Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan.
⁴ RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.
⁵ Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan.
⁶ Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan.
⁷ Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan.
⁸ Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan.
⁹ Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.
¹⁰ Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
¹¹ Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
¹² Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹³ Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹⁴ Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹⁵ Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
¹⁶ Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
¹⁷ Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Abstract

We performed exome-wide association studies to identify single nucleotide polymorphisms that either influence fasting plasma glucose level or blood hemoglobin A_1c content or confer susceptibility to type 2 diabetes mellitus in Japanese. Exome-wide association studies were performed with the use of Illumina Human Exome-12 DNA Analysis or Infinium Exome-24 BeadChip arrays and with 11,729 or 8635 subjects for fasting plasma glucose level or blood hemoglobin A_1c content, respectively, or with 14,023 subjects for type 2 diabetes mellitus (3573 cases, 10,450 controls). The relation of genotypes of 41,265 polymorphisms to fasting plasma glucose level or blood hemoglobin A_1c content was examined by linear regression analysis. After Bonferroni's correction, 41 and 17 polymorphisms were significantly (P < 1.21 × 10^-6) associated with fasting plasma glucose level or blood hemoglobin A_1c content, respectively, with two polymorphisms (rs139421991, rs189305583) being associated with both. Examination of the relation of allele frequencies to type 2 diabetes mellitus with Fisher's exact test revealed that 87 polymorphisms were significantly (P < 1.21 × 10^-6) associated with type 2 diabetes mellitus. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that four polymorphisms (rs138313632, rs76974938, rs139012426, rs147317864) were significantly (P < 1.44 × 10^-4) associated with type 2 diabetes mellitus, with rs138313632 and rs139012426 also being associated with fasting plasma glucose and rs76974938 with blood hemoglobin A_1c. Five polymorphisms-rs139421991 of CAT, rs189305583 of PDCL2, rs138313632 of RUFY1, rs139012426 of LOC100505549, and rs76974938 of C21orf59-may be novel determinants of type 2 diabetes mellitus.

Keywords: blood glycosylated hemoglobin; diabetes mellitus; exome-wide association study; fasting plasma glucose; polymorphism.