title: Replication of genome-wide association signals of type 2 diabetes in Han Chinese in a prospective cohort.
abstract: BACKGROUND
  A recent genome-wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort.
  
  
  METHODS
  Five single nucleotide polymorphisms (SNPs) near the protein tyrosine phosphatase, receptor type, D (PTPRD), SRR, MAF/WWOX, and KCNQ1 genes were genotyped in 1138 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance study.
  
  
  RESULTS
  At baseline, the risk-conferring rs7192960 C allele near the MAF/WWOX genes was associated with lower homoeostasis model assessment of β-cell (HOMA-β) (P = 0·01) and second-phase insulin response in oral glucose tolerance test (OGTT) (P = 0·04). The risk-conferring rs2237897 C alleles in the KCNQ1 gene were associated with higher fasting glucose (P = 0·009), lower HOMA-β (P = 0·03), and lower first-phase insulin response in OGTT (P = 0·03). Over an average follow-up period of 5·43 years, participants with the risk-conferring rs17584499 TT genotype in the PTPRD gene were more likely to progress from nondiabetes to diabetes than were noncarriers (hazard ratio: 8·82, P = 4 × 10(-5) ). The risk-conferring T allele in the PTPRD gene was associated with greater increase in homoeostasis model assessment of insulin resistance (HOMA-IR) (P = 0·04) over time. PTPRD gene expression in human adipose tissues was negatively associated with fasting insulin levels and HOMA-IR.
  
  
  CONCLUSIONS
  Genetic variants near the KCNQ1 and MAF/WWOX genes are associated with reduced insulin secretion. The PTPRD genetic variant appears to be associated with progression to diabetes in Han Chinese, most likely through increased insulin resistance.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road,Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Yen-Feng
authors.initials: YF
authors.lastname: Chiu
authors.forename: Pi-Hua
authors.initials: PH
authors.lastname: Liu
authors.forename: Kuang-Chung
authors.initials: KC
authors.lastname: Shih
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Lin
authors.forename: Wayne H-H
authors.initials: WH
authors.lastname: Sheu
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Jess David
authors.initials: JD
authors.lastname: Curb
authors.forename: Chano A
authors.initials: CA
authors.lastname: Hsiung
authors.forename: Wei-Jei
authors.initials: WJ
authors.lastname: Lee
authors.forename: Po-Chu
authors.initials: PC
authors.lastname: Lee
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D044466:Asian People / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002681:China; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics; D019998:Racemases and Epimerases / Q000235:genetics; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000074584:WW Domain-Containing Oxidoreductase; D000099300:Serine Racemase
chemical_list: D001786:Blood Glucose; D007328:Insulin; D051657:KCNQ1 Potassium Channel; D010088:Oxidoreductases; D051257:Proto-Oncogene Proteins c-maf; D019998:Racemases and Epimerases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099300:Serine Racemase; C496909:KCNQ1 protein, human; C486071:WWOX protein, human; C090899:PTPRD protein, human