title: Common variants in and near IRS1 and subclinical cardiovascular disease in the Framingham Heart Study.
abstract: OBJECTIVE
  Common variants at the 2q36.3-IRS1 locus are associated with insulin resistance (IR), type 2 diabetes (T2D) and coronary artery disease (CAD) in large-scale association studies. We tested the hypothesis that variants at this locus are associated with subclinical atherosclerosis traits.
  
  
  METHODS
  We studied 2740 Framingham Heart Study participants (54.9% women; mean age 57.8 years) with measures of coronary artery or abdominal aortic calcium, internal and common carotid intima-media thickness, and ankle-brachial index (ABI). We tested 1) four SNPs previously shown to be associated with IR (rs2972146, rs2943650), T2D (rs2943641) or CAD (rs2943634) and 2) any SNP at 2q36.3-IRS1, for association with subclinical atherosclerosis traits, adjusting for atherosclerosis risk factors. We set type 1 error rate for test 1) as 0.05/5 traits = P < 0.01, and for test 2) as 0.05 divided by the effective number of independent tests, divided by 5 for the number of traits analyzed.
  
  
  RESULTS
  We found no association between the four known SNPs and subclinical atherosclerosis, but identified one SNP (rs10167219, r(2) with rs2943634 = 0.07) at 2q36.3 that was significantly associated with ABI (corrected P = 0.009). However, rs10167219 was not associated with ABI (P = 0.70) in 35,404 participants in a published ABI association study.
  
  
  CONCLUSIONS
  Common variants at the 2q36.3-IRS1 locus were not associated with subclinical atherosclerosis traits in this study which was adequately powered to find associations with moderate effect size. Although IR and T2D may be mechanistically linked to CAD via subclinical atherosclerosis, an alternate mechanism for the IR-T2D-CAD associations at 2q36.3-IRS1 must be postulated.
authors: General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors: Soo
authors: S
authors: Lim
authors: Jaeyoung
authors: J
authors: Hong
authors: Ching-Ti
authors: CT
authors: Liu
authors: Marie-France
authors: MF
authors: Hivert
authors: Charles C
authors: CC
authors: White
authors: Joanne M
authors: JM
authors: Murabito
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Josée
authors: J
authors: Dupuis
authors: Jose C
authors: JC
authors: Florez
authors: James B
authors: JB
authors: Meigs
mesh_terms: D000368:Aged; D055109:Ankle Brachial Index; D001012:Aorta, Abdominal / Q000473:pathology; D050197:Atherosclerosis / Q000453:epidemiology* / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D061205:Vascular Calcification / Q000453:epidemiology / Q000473:pathology
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins
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