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

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.

[1]  Y. Bang,et al.  Findings of a 1303 Korean whole-exome sequencing study , 2017, Experimental &Molecular Medicine.

[2]  Ali Jazayeri,et al.  Crystal structure of the GLP-1 receptor bound to a peptide agonist , 2017, Nature.

[3]  S. Kwak,et al.  A genetic variant in GLP1R is associated with response to DPP-4 inhibitors in patients with type 2 diabetes , 2016, Medicine.

[4]  Lawrence A Leiter,et al.  Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. , 2016, The New England journal of medicine.

[5]  Stephen C. J. Parker,et al.  The genetic architecture of type 2 diabetes , 2016, Nature.

[6]  J. Buse,et al.  Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. , 2016, The New England journal of medicine.

[7]  Sara M. Willems,et al.  Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease , 2016 .

[8]  T. Shibasaki,et al.  Structure and functional roles of Epac2 (Rapgef4). , 2016, Gene.

[9]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[10]  Andres Metspalu,et al.  Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population , 2014, PLoS genetics.

[11]  Shuang Feng,et al.  RAREMETAL: fast and powerful meta-analysis for rare variants , 2014, Bioinform..

[12]  Thomas Meitinger,et al.  Loss-of-function mutations in SLC30A8 protect against type 2 diabetes , 2014, Nature Genetics.

[13]  Tanya M. Teslovich,et al.  Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility , 2014, Nature Genetics.

[14]  Eric S. Lander,et al.  A polygenic burden of rare disruptive mutations in schizophrenia , 2014, Nature.

[15]  Michael Boehnke,et al.  Recommended Joint and Meta‐Analysis Strategies for Case‐Control Association Testing of Single Low‐Count Variants , 2013, Genetic epidemiology.

[16]  S. Hahn,et al.  Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis , 2013, Diabetologia.

[17]  Xihong Lin,et al.  Rare-variant association testing for sequencing data with the sequence kernel association test. , 2011, American journal of human genetics.

[18]  M. Boehnke,et al.  Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia , 2011, PLoS genetics.

[19]  S. Tatsunami,et al.  Clinical Significance of Urinary Liver-Type Fatty Acid–Binding Protein in Diabetic Nephropathy of Type 2 Diabetic Patients , 2011, Diabetes Care.

[20]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[21]  C. Cobelli,et al.  Common Genetic Variation in GLP1R and Insulin Secretion in Response to Exogenous GLP-1 in Nondiabetic Subjects , 2010, Diabetes Care.

[22]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[23]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[24]  Yasuhiro Sunaga,et al.  The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs , 2009, Science.

[25]  Mika Kivimäki,et al.  Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study , 2009, The Lancet.

[26]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[27]  S. Browning,et al.  A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic , 2009, PLoS genetics.

[28]  S. Leal,et al.  Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. , 2008, American journal of human genetics.

[29]  K. Nanjo,et al.  PAX4 mutations in Thais with maturity onset diabetes of the young. , 2007, The Journal of clinical endocrinology and metabolism.

[30]  Ho-Young Son,et al.  Epidemic obesity and type 2 diabetes in Asia , 2006, The Lancet.

[31]  P. Gruss,et al.  The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas , 1997, Nature.

[32]  H. Min,et al.  Non‐insulin‐dependent Diabetes Mellitus (NIDDM) in Korea , 1996, Diabetic medicine : a journal of the British Diabetic Association.

[33]  E. Kohner,et al.  Report of the Visual Handicap Group. , 1996, Diabetic medicine : a journal of the British Diabetic Association.

[34]  BOULIN,et al.  Classification and Diagnosis of Diabetes. , 2022, Primary care.

[35]  S. Kwak,et al.  10-year trajectory of β-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study. , 2016, The lancet. Diabetes & endocrinology.

[36]  Loss-of-function mutations in SLC 30 A 8 protect against type 2 diabetes , 2014 .

[37]  Shamil R Sunyaev,et al.  Pooled association tests for rare variants in exon-resequencing studies. , 2010, American journal of human genetics.

[38]  Standards of medical care in diabetes. , 2005, Diabetes care.

[39]  Claude-Alain H. Roten,et al.  Theoretical and practical advances in genome halving , 2004 .

[40]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[41]  A. Estreicher,et al.  The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6 , 2002, Diabetologia.