title: Variation in inflammation-related genes and risk of incident nonfatal myocardial infarction or ischemic stroke.
abstract: BACKGROUND
  From initiation to plaque rupture, immune system components contribute to atherosclerosis. We investigated variation in inflammation-related genes - interleukin (IL)-1beta, IL-6, C-reactive protein (CRP), IL-10, IL-18, and the tumor necrosis factor (TNF) superfamily [lymphotoxin(LT)-alpha, TNF-alpha, LT-beta] - with respect to nonfatal incident myocardial infarction (MI) or ischemic stroke risk.
  
  
  RESULTS
  A population-based case-control study recruited postmenopausal and/or hypertensive Group Health members aged 30-79 years. We chose a subset of single nucleotide polymorphisms (SNPs) to describe common gene-wide variation on the basis of linkage disequilibrium. 36 SNPs, describing 38 common haplotypes for 5 genes and a 3-gene cluster, were genotyped among 856 MI cases, 368 stroke cases, and 2688 controls. Associations of SNPs or PHASE-inferred haplotypes and risk were estimated using logistic regression; significance of gene-level associations was assessed with global Wald tests and permutation tests. Gene-wide IL-18 variation was associated with higher MI risk and an IL-1B haplotype was associated with lower stroke risk. In secondary analyses of SNPs, we observed associations of several IL-1B polymorphisms with risk of MI or stroke. IL-6, CRP, IL-10, and TNF superfamily gene variation was not associated with MI or stroke risk.
  
  
  CONCLUSIONS
  Our results support prior reports associating an IL-18 gene variant and MI risk, contribute additional evidence to reports of IL-1B and cardiovascular risk, and fail to confirm risk differences previously observed for CRP, IL-6, and TNF-alpha promoter variants.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 981041, USA. joshbis@u.washington.edu
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Reiner
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Marciante
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Enquobahrie
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Monks
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
mesh_terms: D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D002097:C-Reactive Protein / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D002537:Intracranial Arteriosclerosis / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D053308:Lymphotoxin-beta / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D014657:Vasculitis / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology
chemical_list: D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; C505886:LTB protein, human; D053308:Lymphotoxin-beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002097:C-Reactive Protein