Abstract 3453: Genetically Elevated C-reactive Protein Does Not Cause Ischemic Heart Disease: Three Mendelian Randomization Studies
Elevated levels of C-reactive protein (CRP) associate with increased risk of ischemic heart disease (IHD). Whether this is a causal effect is unclear. We tested this hypothesis using a Mendelian randomization design. To do so, we first tested whether CRP levels associate with IHD, and secondly we examined whether SNPs in the CRP gene associate with both elevated CRP levels and increased risk of IHD. Prospectively we followed 9238 persons from the Copenhagen City Heart study for 30 years, during which 1421 developed IHD. Cross-sectionally we examined 26190 persons from The Copenhagen General Population Study, of which 753 had IHD. Finally, we compared 2468 IHD cases versus 9872 controls. In all 3 studies, 3 CRP SNPs were determined: rs1205, rs1130864 and rs3091244. Both in the prospective and in the cross-sectional study, hsCRP-levels were determined. Upper versus lower tertile of CRP-levels predicted prospectively a 2.1-fold and cross-sectionally a 1.4 fold increased risk of IHD. Although the 3 CRP SNPs associated with up to a 35% reduction and up to a 67% increase in CRP levels, these genotypes did not associate with reduced or increased risk of IHD (figure⇓). In conclusion, as expected elevated CRP-levels predicted increased risk of IHD. However, although SNPs in the CRP-gene associated with marked changes in CRP-levels, these SNPs did not predict risk of IHD. Therefore, elevated CRP levels do not cause IHD.