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

Soo Heon Kwak; Jeesoo Chae; Seungbok Lee; Sungkyoung Choi; Bo Kyung Koo; Ji Won Yoon; Jin-Ho Park; Belong Cho; Min Kyong Moon; Soo Lim; Young Min Cho; Sanghoon Moon; Young Jin Kim; Sohee Han; Mi Yeong Hwang; Yoon Shin Cho; Myung-Shik Lee; Jang, Hak C.; Hyun Min Kang; Taesung Park

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.

TYPE 2 diabetes; CARBOHYDRATE intolerance; ENDOCRINE diseases; GLUCOSE metabolism disorders; NUTRITION disorders

Diabetes, 2018, Vol 67, Issue 9, p1892

0012-1797

Academic Journal

10.2337/db18-0361