Objective: To examine the robustness of the association between C-reactive protein (CRP) levels and increased risk of venous thromboembolism (VTE) and to examine whether genetically elevated CRP levels cause VTE.
Methods and results: In the prospective Copenhagen City Heart Study, we observed 10 388 participants for longer than 16 years, of whom 484 developed a VTE. In the cross-sectional Copenhagen General Population Study, we studied 36 616 participants, of whom 903 previously had a VTE. Levels of CRP greater than 3 mg/L versus less than 1 mg/L were associated with a 2.3- and 2.4-fold increased risk of VTE in the Copenhagen City Heart Study and the Copenhagen General Population Study, respectively. CRP levels in tertiles, quintiles, and octiles associated with a stepwise increase in VTE risk. CRP genotypes associated with an increase in plasma CRP levels up to 59% but did not associate consistently with risk of VTE in either study. The causal odds ratio for VTE for a doubling in genetically elevated CRP on instrumental variable analyses was lower than the odds ratio for VTE observed for a doubling in plasma CRP on logistic regression ([odds ratio and 95% CI] 0.80 [0.56 to 1.12] versus 1.17 [1.08 to 1.27]; P=0.04).
Conclusions: We observed 47,000 participants from the general population, of whom 1387 developed VTE. Although elevated CRP levels robustly associated with increased risk of VTE, this may not necessarily be a causal association because genetically elevated CRP did not associate with VTE risk.