Complement Factor H Polymorphism, Inflammation, and Age–Related Macular Degeneration in the Rotterdam Study

Abstract

Purpose: : An association between the complement factor H (CFH) gene, a regulator of complement, and age–related macular degeneration (AMD) was demonstrated in case–control studies.We assessed the relevance of CFH for AMD in a large Caucasian population, and investigated potentially modifying risk factors.

Methods: : We determined the frequency of the Y402H polymorphism of CFH in 5681 participants of the population–based Rotterdam Study, assessed early and late AMD at baseline and during 30,621 person–years of follow–up, and calculated risks of AMD. We then related these risks to serum markers of inflammation, smoking, and genetic variation of C–reactive protein (CRP).

Results: : The frequency of Y402H was 36.2%. The odds ratio (OR) of AMD increased in an allele–dose manner with clinical severity with OR 2.71 (95% CI 2.10, 3.50) of early AMD, and OR 11.02 (6.82, 11.81) of late AMD for homozygous persons. Absolute risks of late AMD by age 95 were 48.3% for homozygotes, 42.6% for heterozygotes, and 21.9% for non–carriers. The population attributable risk of Y402H was 54.0%. Elevated erythrocyte sedimentation rates further increased risks to OR 20.2 (95% CI 9.5, 43.0), elevated serum CRP to OR 27.7 (10.7, 72.0), and smoking to OR 34.0 (13.0, 88.6) for homozygotes compared to non–carriers without these determinants. CRP haplotypes conferring high CRP levels further increased the effect of Y402H (P<0.008).

Conclusions: : The CFH polymorphism Y402H accounts for the majority of AMD in the general population, and is particularly hazardous in the presence of environmental and genetic stimulators of the complement cascade.

Keywords: age-related macular degeneration • genetics • clinical (human) or epidemiologic studies: risk factor assessment