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)-1β, IL-6, C-reactive protein (CRP), IL-10, IL-18, and the tumor necrosis factor (TNF) superfamily [lymphotoxin(LT)-α, TNF-α, LT-β] – with respect to nonfatal incident myocardial infarction (MI) or ischemic stroke risk. Methods and 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-α promoter variants.