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Nonsynonymous Variants in PAX4 and GLP1R 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 Moon4  ;  Soo Lim  ;  Young Min Cho  ;  Sanghoon Moon  ;  Young Jin Kim  ;  Sohee Han  ;  Mi Yeong Hwang  ;  Yoon Shin Cho  ;  Myung-Shik Lee  ;  Hak C. Jang  ;  Hyun Min Kang  ;  Taesung Park  ;  Nam H. Cho  ;  Kyunga Kim  ;  Jong-Il Kim  ;  Kyong Soo Park 
 DIABETES, Vol.67(9) : 1892-1902, 2018 
Journal Title
Issue Date
Aged ; Alleles ; Amino Acid Substitution ; Asian Continental Ancestry Group ; Case-Control Studies ; Cohort Studies ; Computational Biology ; Databases, Genetic ; Diabetes Mellitus, Type 2/genetics* ; Diabetes Mellitus, Type 2/metabolism ; Expert Systems ; Female ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease* ; Genetic Variation* ; Genome-Wide Association Study ; Glucagon-Like Peptide-1 Receptor/chemistry ; Glucagon-Like Peptide-1 Receptor/genetics* ; Glucagon-Like Peptide-1 Receptor/metabolism ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/genetics* ; Homeodomain Proteins/metabolism ; Humans ; Male ; Middle Aged ; Paired Box Transcription Factors/chemistry ; Paired Box Transcription Factors/genetics* ; Paired Box Transcription Factors/metabolism ; Polymorphism, Single Nucleotide* ; Republic of Korea ; Whole Exome Sequencing
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
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