A Prospective Assessment of the Y402H Variant in Complement Factor H, Genetic Variants in C-Reactive Protein, and Risk of Age-Related Macular Degeneration

Abstract

Two biologically related factors, complement factor H (CFH) and C-reactive protein (CRP), have been associated with AMD. The Y402H variant of CFH is located within the binding site of CFH for CRP. Although plasma CRP levels have been related to AMD and plasma CRP levels are partly determined by genetic variation, there is no information on whether genetic variants in CRP are associated with AMD. A prospective analysis was performed of 111 men who eventually developed AMD and 401 men who remained free of AMD, all participants in the Physicians' Health Study. Genotypes were determined for the common T-->C single nucleotide polymorphism (SNP) in exon 9 of CFH (rs1061170; protein Y402H), as well as seven previously described CRP SNPs (rs3093059, rs2794521, rs3091244, rs1417938, rs1800947, rs1130864, and rs1205). Logistic regression analysis was used to evaluate individual SNPs, as well as six CRP haplotypes for association with AMD. The high-risk C allele of CFH was present in 45% of cases and 34% of controls. An odds ratio (OR) of 1.46 was observed for AMD (95% confidence interval [CI]: 1.05-2.04) for TC heterozygotes and an OR of 2.13 (95% CI: 1.10-4.16) for CC homozygotes, assuming a multiplicative (log-additive) model and attributable fraction of 25% (95% CI: 1% to 44%) was calculated. For CRP, single-marker or haplotype-based analysis failed to reveal any significant associations with a risk of AMD. These prospective data confirmed an association between the Y402H variant of CFH and a risk of AMD. In contrast, although a biologically plausible, genetic variation in CRP does not appear to be associated with a risk of AMD. Further prospective studies of a larger number of subjects are needed to substantiate available information on the genetic epidemiology of AMD.