title: IRS1 gene variants, dysglycaemic metabolic changes and type-2 diabetes risk.
abstract: OBJECTIVE
  A recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk.
  
  
  RESULTS
  We genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80-1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69-0.96, p = 0.015).
  
  
  CONCLUSIONS
  We confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.
authors.affiliation: Harokopio University of Athens, 17671 Athens, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Yiannakouris
authors.forename: J A
authors.initials: JA
authors.lastname: Cooper
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.forename: F
authors.initials: F
authors.lastname: Drenos
authors.forename: H A
authors.initials: HA
authors.lastname: Ireland
authors.forename: J W
authors.initials: JW
authors.lastname: Stephens
authors.forename: K-W
authors.initials: KW
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Elkeles
authors.forename: I F
authors.initials: IF
authors.lastname: Godsland
authors.forename: M
authors.initials: M
authors.lastname: Kivimaki
authors.forename: A D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: M
authors.initials: M
authors.lastname: Kumari
authors.forename: P J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: S E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism*; D005060:Europe; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D015810:Linkage Disequilibrium; D016015:Logistic Models; D015999:Multivariate Analysis; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins