Abstract
BackgroundC-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD).Methods and FindingsWe conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses' Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A>T and 4741G>C, but associated with lower CRP levels for SNPs 2667G>C and 3872C>T. SNP 2667G>C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01–2.44); p = 0.047] and men [1.93 (95% CI 1.30–2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations.ConclusionsCommon variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene.
Highlights
Inflammatory processes are involved in the initiation and progression of atherosclerotic lesions, as well as in the development of atheroma complications,[1] and markers of inflammation may reflect subclinical vascular inflammation and be useful diagnostic tools.[2]
Recent family studies suggest heritability estimates of C-reactive protein (CRP) ranging from 27–40%,[11,12] and it is hypothesized that genetic variation in the CRP gene may influence plasma CRP levels and subsequent risk of coronary heart disease (CHD)
The pairwise linkage disequilibrium (LD) measures and correlation coefficients between CRP polymorphisms were analyzed among the control women and men (Table 3)
Summary
Inflammatory processes are involved in the initiation and progression of atherosclerotic lesions, as well as in the development of atheroma complications,[1] and markers of inflammation may reflect subclinical vascular inflammation and be useful diagnostic tools.[2]. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A.T and 4741G.C, but associated with lower CRP levels for SNPs 2667G.C and 3872C.T. SNP 2667G.C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01–2.44); p = 0.047] and men [1.93 (95% CI 1.30–2.88); p = 0.001]. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene
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