Zacho J et al. (2008) Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 359: 1897–1908

Elevated levels of C-reactive protein (CRP) are associated with an increased risk of ischemic vascular disease, but whether this association is causal has not been determined. Study of genetic variants provides a relatively unbiased analysis of association, because gene assortment occurs randomly. Thus, Zacho et al. examined whether genetic variants that elevate levels of CRP throughout life increase the risk of ischemic cerebrovascular disease and ischemic heart disease. The analysis involved four large, independent cohorts, and included >50,000 Danish people in total.

First, in a multivariate analysis, the researchers showed that the risk of ischemic cerebrovascular disease was increased by a factor of 1.3 and that of ischemic heart disease was increased by a factor of 1.6 in people who had a CRP level >28.6 nmol/l, compared with those who had levels <9.5 nmol/l. The researchers next showed that genotype combinations involving four different CRP polymorphisms were associated with increases of up to 64% in lifelong CRP levels, which would theoretically predict an increased risk of up to 25% and up to 32% for ischemic cerebrovascular disease and ischemic heart disease, respectively. Nevertheless, CRP genotypes were not associated with increases in the risks of either ischemic cerebrovascular disease or ischemic heart disease.

The researchers conclude that CRP level is a marker for an increased risk of ischemic vascular disease, but is not causally related to the increased risk.