Increased levels of C-Reactive Protein (CRP) are associated with an increased risk of ischaemic heart and cerebrovascular disease. But is CRP a causal factor in atherosclerosis development or merely a marker for ischaemic vascular disease? Evidence to suggest a role for CRP in the pathogenesis of atherosclerosis is predominantly from epidemiological studies. These have consistently observed an association between elevated CRP and cardiovascular events. This relationship has the same statistical strength as for other cardiovascular risk factors such as hypertension and diabetes mellitus. However statistical strength does not imply causality as alternative explanations may be offered by reverse causality or other confounding factors. ‘Mendelian randomisation’ – the random assortment of genes that occurs during gamete formation – provides a relatively unbiased method in assessing whether risk factors that have a genetic component are causally related to clinical outcomes.
Four independent cohorts of white people of Danish descent were studied – a total number of 50,816 subjects. These independent cohorts allowed independent confirmation of the findings in each group. The investigators utilised the fact that genetic variation in the CRP gene gives rise to variation in plasma CRP levels. The risk of ischaemic heart disease and ischaemic cerebrovascular disease were increased by a factor of 1.6 and 1.3 respectively in patients with a CRP level >3mg/l as compared to those with a CRP <1mg/l. Genotype combinations of 4 CRP polymorphisms studied were associated with an increase in CRP levels of up to 64%. This theoretically predicts an increased risk of up to 32% for ischaemic heart disease and up to 25% for ischaemic vascular disease. However these genotype combinations were not associated with an increased risk of ischaemic vascular disease either singly or in combination. A positive control was included in the study – variations in the apolipoprotein E level which is known to affect cholesterol. The predicted association between these variants and increased cardiovascular risk was identified.
Limitation of this study include the use of cross-sectional and case control cohorts as use of subjects recruited after the event can introduce survival bias. It cannot be ruled out that the CRP polymorphisms studied are related to higher plasma levels of a less functionally active CRP. It assumes that genetically elevated CRP levels behave in a similar fashion to acquired elevations and that lifelong CRP elevation does not induce compensatory mechanisms in other systems. There may also be confounding from other genes in ‘linkage disequilibrium with the CRP polymorphisms studied.
Nonetheless, the results appear to suggest that CRP is not causally implicated in the pathogenesis of atherosclerosis. More definitive answers may follow from trials involving agents aimed specifically at CRP lowering.
- Zacho J, Tybjaerg-Hansen A, Jensen JS et al. Genetically elevated C-Reactive Protein and Ischaemic Vascular Disease. N Engl J Med 2008;359:1897-908
- Schunkert H and Samani NJ (ed). Elevated C-Reactive Protein in Atherosclerosis – Chicken or Egg? N Engl J Med 2008;359:1953-5