Complement factor H Y402H decreases cardiovascular disease risk in patients with familial hypercholesterolaemia

Aims Activation of the complement system seems an important link between inflammation and atherogenesis. The Y402H polymorphism of complement factor H (CFH) has been associated with cardiovascular events, but results are conflicting and possibly modified by age of onset of cardiovascular disease (CVD). Methods and results We determined whether or not the Y402H polymorphism influenced CVD risk in a multicentre cohort study involving 2016 unrelated patients with familial hypercholesterolaemia (FH), who have an extremely increased susceptibility to premature CVD. We identified 261 individuals who were homozygous for the polymorphism (CC genotype; 12.9%), 929 individuals who were heterozygous (TC genotype; 46.1%), and 826 individuals carried the wild-type (TT genotype; 41.0%). During 95 115 person years, 644 patients had a cardiovascular event. Carriers of the CC genotype had a decreased risk of CVD (hazard ratio 0.67, 95% confidence interval 0.51–0.87; P = 0.003) relative to the other genotype groups. This association was unaltered after adjustment for clinically relevant cardiovascular risk factors or age effects. Conclusion Among patients with severely increased risk of early onset CVD, the Y402H CFH variant was inversely associated with susceptibility to CVD. This suggests that CFH is a modifier gene of CVD.