Fibrinogen, C-reactive protein and coronary heart disease: does Mendelian randomization suggest the associations are non-causal?

Two recent reviews in QJM have evaluated the role of fibrinogen1 and C-reactive protein (CRP)2 as risk factors for cardiovascular disease. Both raised fibrinogen and CRP levels clearly predict future risk of cardiovascular events, and could be used to identify those patients who would get the greatest absolute benefit from intervention targeting blood pressure and cholesterol lowering, smoking cessation or exercise promotion. The reviews also raise the issue of a causal relationship between fibrinogen or CRP and cardiovascular disease, and discuss the roles of pharmacological or lifestyle changes as means of modifying fibrinogen or CRP levels.1,,2 However, doubt is cast on the causal nature of either factor by evidence produced by studies using the ‘Mendelian randomization’ paradigm.3 Here we briefly outline Mendelian randomization, and review what studies using this approach have to say regarding the potential causal roles of fibrinogen and CRP with respect to cardiovascular disease. Epidemiology aims to inform public-health strategies by identifying modifiable risk factors for disease. However, in the past decade, several well-publicized examples of the misleading identification of such factors by observational epidemiological studies have been reported: β-carotene and cancer; vitamin C and coronary heart disease; and hormone replacement therapy and cardiovascular disease among them. In observational epidemiological studies these factors appeared to have clinically important protective effects, but randomized controlled trials demonstrated that they were, if anything, harmful. The probable reason for these misleading findings in the observational studies is that there is considerable confounding between, for example, vitamin C consumption (or taking β-carotene supplements) and various behavioural and socio-economic factors related to increased risk of disease. Because of measurement problems, observational epidemiology simply cannot deal with this issue (despite valiant attempts—and strident claims—to the contrary). Genetic epidemiology is often seen as the antipathy of public-health epidemiology, but …