Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, Gaffney D, Packard CJ, O'Reilly DS, Juhan-Vague I, Yudkin JS, Tremoli E, Margaglione M, Di Minno G, Hamsten A, Kooistra T, Stephens JW, Hurel SJ, Livingstone S, Colhoun HM, Miller GJ, Bautista LE, Meade T, Sattar N, Humphries SE, Hingorani AD. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol. 2006;35(4):922-31.

BACKGROUND: It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded.METHODS: We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies).RESULTS: CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs.CONCLUSIONS: A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.