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

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

Author information

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 A1c 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 A1c 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 A1c 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 A1c 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 A1c. 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

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

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