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Diabetes. 2018 Sep;67(9):1892-1902. doi: 10.2337/db18-0361. Epub 2018 Jun 25.

Nonsynonymous Variants in PAX4 and GLP1R Are Associated With Type 2 Diabetes in an East Asian Population.

Author information

1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
2
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
3
Research Institute of Basic Sciences, Seoul National University, Seoul, Republic of Korea.
4
Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
5
Department of Internal Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea.
6
Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
7
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
8
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
9
Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Cheongju, Republic of Korea.
10
Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea.
11
Severance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
12
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.
13
Department of Statistics, Seoul National University, Seoul, Republic of Korea.
14
Department of Preventive Medicine and Public Health, Ajou University School of Medicine, Suwon, Republic of Korea.
15
Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea.
16
Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
17
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea kspark@snu.ac.kr.
18
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.

Abstract

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 × 10-16 and OR 0.84, P = 3.55 × 10-8, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 × 10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 × 10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

PMID:
29941447
DOI:
10.2337/db18-0361
[Indexed for MEDLINE]
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