title: Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations.
abstract: OBJECTIVE
  Recent genome-wide association (GWA) studies and subsequent replication studies have greatly increased the number of validated type 2 diabetes susceptibility variants, but most of these have been conducted in European populations. Despite the high prevalence of the disease in South Asians, studies investigating GWA-validated type 2 diabetes risk variants in this ethnic group are limited. We investigated 30 single nucleotide polymorphisms (SNPs), predominantly derived from recent GWA studies, to determine if and to what extent these variants affect type 2 diabetes risk in two Punjabi populations, originating predominantly from the District of Mirpur, Pakistan.
  
  
  METHODS
  Thirty SNPs were genotyped in 1,678 participants with type 2 diabetes and 1,584 normoglycaemic control participants from two populations; one resident in the UK and one indigenous to the District of Mirpur.
  
  
  RESULTS
  SNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, HHEX/IDE, IGF2BP2, SLC30A8, KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 displayed significant (p < 0.05) associations with type 2 diabetes, with similar effect sizes to those seen in European populations. A constructed genetic risk score was associated with type 2 diabetes (p = 5.46 × 10(-12)), BMI (p = 2.25 × 10(-4)) and age at onset of diabetes (p = 0.002).
  
  
  CONCLUSIONS
  We have demonstrated that 13 variants confer an increased risk of type 2 diabetes in our Pakistani populations; to our knowledge this is the first time that SNPs in or near KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 have been significantly associated with the disease in South Asians. Large-scale studies and meta-analyses of South Asian populations are needed to further confirm the effect of these variants in this ethnic group.
authors.affiliation: Diabetes Research Laboratory, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK. s.d.rees@bham.ac.uk
authors.forename: S D
authors.initials: SD
authors.lastname: Rees
authors.forename: M Z I
authors.initials: MZ
authors.lastname: Hydrie
authors.forename: A S
authors.initials: AS
authors.lastname: Shera
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: J P
authors.initials: JP
authors.lastname: O'Hare
authors.forename: A H
authors.initials: AH
authors.lastname: Barnett
authors.forename: A
authors.initials: A
authors.lastname: Basit
authors.forename: M A
authors.initials: MA
authors.lastname: Kelly
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D056970:Co-Repressor Proteins; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010154:Pakistan; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C430460:JAZF1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009363:Neoplasm Proteins