Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease

Abstract

Conclusion: Polymorphisms of the C-reactive protein (CRP) gene are associated with increases in CRP levels but are not in themselves associated with an increased risk of ischemic vascular disease. Summary: It is well known that elevated plasma levels of CRP are associated with an increased risk of ischemic cerebrovascular and ischemic cardiac disease. What is unknown is whether CRP levels themselves contribute to causation of ischemic cerebrovascular or cardiac disease, or are merely markers of the existence of ischemic cerebrovascular or cardiovascular disease. The CRP gene has genetic variations that increase levels of CRP to different degrees and therefore can theoretically be used to assess the consequences of lifelong high CRP levels independent of additional risk factors. The authors of this study sought to determine whether genetically elevated CRP levels caused an increased risk of ischemic heart disease and ischemic cerebrovascular disease. The study included 10,276 people from a general population cohort. Ischemic heart disease developed in 1786, and ischemic cerebrovascular disease developed in 741. In an additional cohort of 31,992 persons from the general population, 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. The authors also studied an additional 2238 patients with ischemic heart disease and 4474 control participants along with 612 patients with ischemic cerebrovascular disease and an additional 1224 control participants. High-sensitivity CRP was measured, followed with genotyping of four CRP polymorphisms and two apolipoprotein E polymorphisms. In persons with CRP levels >3 mg/L, compared with those with CRP levels <1 mg/L, ischemic heart disease was increased by a factor of 1.6 and ischemic cerebrovascular disease was increased by a factor of 1.3. The four CRP polymorphisms resulted in an increase in CRP levels of up to 64%. Theoretically, this would predict an increased risk of 32% for ischemic heart disease and 25% for ischemic cerebrovascular disease. However, no genotype combination was associated with an increased risk of either ischemic cerebrovascular or ischemic cardiac disease. Apolipoprotein E genotypes were associated with an increased risk of ischemic heart disease and elevated cholesterol levels. Comment: Drugs are being developed to specifically target lowering CRP levels (Curr Atheroscler Rep 2006;8:421-8). The ultimate goal would be to lower CRP levels and, if CRP is associated with causing atherosclerosis, ultimately prevent the development of vascular disease. This study suggests that such a strategy is likely to be “barking up the wrong tree.” Although epidemiologic studies have observed an increased risk of ischemic vascular disease associated with higher plasma CRP levels, the current data indicate that increased CRP levels are perhaps more a marker for atherosclerosis than a cause of atherosclerosis. Please see also the abstract for a related article (N Engl J Med 2008;359:2195-207).