Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration

Abstract

To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within AMD-associated loci and pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2×10−8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association to disease. We observed significant association with rare missense alleles outside CFI. Genotyping in 5,115 independent samples confirmed associations to AMD with a K155Q allele in C3 (replication p=3.5×10−5, OR=2.8; joint p=5.2×10−9, OR=3.8) and a P167S allele in C9 (replication p=2.4×10−5, OR=2.2; joint p=6.5×10−7, OR=2.2). Finally, we show that the 155Q allele in C3 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

“…17,79 FH is the major plasma regulatory protein of the AP; its cellular (membrane) counterpart in nonrodent primates is CD46. 29e32 CD46 is expressed nearly ubiquitously in humans.…”

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

“…This binds to and stabilises C3 convertase, leading to the activation of the alternative complement factor pathway and excessive consumption of C3 (Misra et al, 2004;Savage et al, 2009). Increased activity of C3 convertase activity has also been proposed as a risk for developing AMD (Helgason et al, 2013;Seddon et al, 2013;Zhan et al, 2013). High-risk alleles in CFH similarly act in this pathway.…”

Common variant rs10033900 near the complement factor I gene is associated with age-related macular degeneration risk in Han Chinese population

“…28,29 For example, van de Ven et al 29 identified a rare, highly penetrant missense mutation c.355G4A (p.(Gly119Arg); RefSeq NM_000204.3) that confers a high risk of AMD (OR, 22.20; P ¼ 3.79 Â 10 À6 ) via the regulation of C3b degradation. Although this likely causal mutation was also identified by Seddon et al, 28 the individual mutation showed no associations with AMD (P ¼ 0.24); 28 instead, the burden of rare functional CFI variant enrichment in this gene was significantly increased in AMD cases (OR, 3.6; P ¼ 2.0 Â 10 À8 ), indicating the combined effects of multiple rare mutations on the modulation of AMD risk. 28 Therefore, these rare variant studies have provided important implications for causal SNPs or mutations related to AMD in the Chinese population.…”