Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) features excessive complement activation, including the release and deposition of proinflammatory fragments in the retina. Genetic evidence also directly implicates the role of complement activation in disease (reviewed in Refs. 1–9). One of the first reproducible genome-wide association study findings was the rs1061170 (Y402H) polymorphism in complement factor H (CFH).10 An intronic single-nucleotide polymorphism (SNP) in CFH, rs1410996, was also independently associated with AMD, with the minor allele conferring a similar risk of disease.11 Common SNPs near the gene for the regulator complement factor I (CFI),12 and in the genes for the complement component 3 (C3)13,14 and the complement protease factor B (CFB)11,15 were also associated with disease. Carrying risk alleles in these genes leads to a lifetime AMD risk of nearly 50%.11,14,16,17 Factor H (FH) is a key inhibitor of the alternative pathway (AP) of complement activation.18,19 It is an abundant (average level, ∼300 μg/mL) serum protein that negatively regulates the C3 convertase of the alternative pathway. To accomplish this task, FH competes with factor B (FB) in binding to C3b and decays both the proconvertase (C3bB) and the active C3 convertase (C3bBb). Further, it serves as a cofactor protein for the serine protease factor I (FI)–mediated cleavage of C3b to hemolytically inactive iC3b. The latter cannot serve as a nidus for formation of the AP's positive feedback/amplification loop, in contrast to C3b. In the era of next-generation sequencing, AMD has provided one of the first examples of rare variants increasing the risk of a common disease. A rare, penetrant variant in CFH coding for R1210C was associated with AMD with an odds ratio (OR) of approximately 20, representing the strongest risk factor for AMD to date.20 This variant was present in only two individuals (minor allele frequency [MAF] = 0.015%) in the NHLBI 6500 exome sequencing project (6500 ESP). Additionally, a single missense variant in C3, K155Q, was found by three independent groups to be associated with AMD.21–23 Variant K155Q was present at a frequency of 0.4% in European Americans sequenced as part of the 6500 ESP. A diversity of rare and private variants in CFI was also found to be associated with AMD in a large targeted sequencing study.21 Two reports of additional rare CFH variants linked to AMD within families have been published.24,25 In one report using whole-exome sequencing, two different variants segregated with disease in two unrelated families.24 Both variants had similar detrimental effects on function. In the other report, a rare variant in the same domain as the common predisposing variant Y402H was identified in an affected Amish family.25 In this report, our goal was to assess the presence of rare variants in CFH in patients with advanced AMD (A-AMD). The prior observations of a remarkable number of rare variants in CFI in A-AMD,21 the striking association of common variants in CFH with AMD,1–5,10,11 and two reports of rare CFH variants with high penetrance in families24,25 suggested that there should be rare variants with a large effect size in CFH. To this end, we analyzed data from our targeted sequencing study with a focus on the coding region of CFH, especially its functional domains.