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

Authors
Kwak, SH; Chae, J; Lee, S; Choi, S; Koo, BK; Yoon, JW; Park, JH; Cho, B; Moon, MK; Lim, S; Cho, YM; Moon, S; Kim, YJ; Han, S; Hwang, MY; Cho, YS; Lee, MS; Jang, HC; Kang, HM; Park, T; Cho, NH; Kim, K; Kim, JI; Park, KS
Citation
Diabetes, 67(9):1892-1902, 2018
Journal Title
Diabetes
ISSN
0012-17971939-327X
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 x 10(-16) and OR 0.84, P = 3.55 x 10(-8), respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 x 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 x 10(-4)). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.
MeSH terms
AgedAllelesAmino Acid SubstitutionAsian Continental Ancestry GroupCase-Control StudiesCohort StudiesComputational BiologyDatabases, GeneticDiabetes Mellitus, Type 2/genetics*Diabetes Mellitus, Type 2/metabolismExpert SystemsFemaleGene FrequencyGenetic Association StudiesGenetic Predisposition to Disease*Genetic Variation*Genome-Wide Association StudyGlucagon-Like Peptide-1 Receptor/chemistryGlucagon-Like Peptide-1 Receptor/genetics*Glucagon-Like Peptide-1 Receptor/metabolismHomeodomain Proteins/chemistryHomeodomain Proteins/genetics*Homeodomain Proteins/metabolismHumansMaleMiddle AgedPaired Box Transcription Factors/chemistryPaired Box Transcription Factors/genetics*Paired Box Transcription Factors/metabolismPolymorphism, Single Nucleotide*Republic of KoreaWhole Exome Sequencing
DOI
10.2337/db18-0361
PMID
29941447
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Preventive Medicine & Public Health
AJOU Authors
조, 남한
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