Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype

Abstract

Background: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.

Methods: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry.

Results: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.

Conclusion: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Figure 1

Main effect of Y402H on late AMD risk, and other subtypes of AMD in European populations. Per-allele effect estimates are shown for the effect of Y402H on the outcome of late AMD (GA and CNV) from published and newly genotyped studies. Data on discrete subtypes of late AMD (GA and CNV) were available from 10 studies (see Supplementary Table S1 for studies providing these data), and estimates from a further four published studies contributed to the early AMD estimate. Any AMD included all subtypes (early and late), this estimate being calculated from newly genotyped and published studies. Heterogeneity was tested across groups of late AMD (GA and CNV) and across GA, CNV and early AMD. *Indicates heterogeneity between total late AMD and early AMD

Figure 2

Association of Y402H genotype and AMD risk by subtype stratified by smoking habit

Figure 3

Frequency of Y402H genotypes in controls of different ethnicities (genotype counts are given in Supplementary Table S2)