A rare penetrant mutation in CFH confers high risk of age-related macular degeneration

Abstract

Two common variants within CFH, the Y402H1–4 and the rs1410996 SNPs5,6, explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high throughput sequencing to discover a rare high-risk CFH haplotype containing an R1210C mutation. This allele has been implicated previously in atypical hemolytic uremic syndrome, and abrogates C-terminal ligand binding7,8. Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, p=7.0×10−6) and six year earlier onset of disease (p=2.3×10−6). This result suggests that loss of function alleles at CFH likely drive AMD risk. This finding represents one of the first instances where a common complex disease variant has led to discovery of a rare penetrant mutation.

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

“…Malondialdehyde is a natural byproduct of lipid peroxidation, suggesting that oxidative stress and complement dysregulation may act through a common mechanism. The association between AMD and CFH was further strengthened with the demonstration that a rare allele causing a R1210C substitution in CFH is a highly penetrant cause of AMD (3).…”

“…Inflammation, oxidative stress, high-fat diets, light exposure, and genetic factors all contribute to the pathogenesis of AMD (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Among the genetic determinants for AMD, the gene for complement factor H (CFH) is a strong susceptibility locus (4 -7).…”

“…Age-related macular degeneration (AMD) 3 is a common cause of visual loss in the elderly (1,2). Inflammation, oxidative stress, high-fat diets, light exposure, and genetic factors all contribute to the pathogenesis of AMD (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

“…Among these correlations, mutations that alter the C-terminal region of FH are prototypical of aHUS, 7-9 whereas the Y402H polymorphism in SCR7 of FH is a unique risk factor for AMD [10][11][12][13] and complete FH deficiency or homozygous mutations in the N-terminal region of FH associate with C3G. 14,15 In this context, the association of the C-terminal FH-R1210C mutation with aHUS, 16 AMD, [17][18][19] and C3G 2 0 challenges these genotypephenotype correlations, suggesting previously unrecognized pathogenic links between these disorders. Here, we performed experiments to reveal the molecular basis of these associations and to identify what determines the disease outcome in FH-R1210C carriers.…”

A Biologically Informed Method for Detecting Associations with Rare Variants

“…Rare variants can be in LD with other variants; rare haplotypes exist and can be associated with disease [50]. However, indirect association testing assumes low-level allelic heterogeneity and assumes that the variants are common [21,44].…”