Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations

Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMDassociated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p ¼ 2.4 3 10 À10 ; FHR-2, p ¼ 6.0 3 10 À10 ; FHR-3, p ¼ 1.5 3 10 À5 ; FHR-4, p ¼ 1.3 3 10 À3 ; FHR-5, p ¼ 1.9 3 10 À4 ) and FHL-1 (p ¼ 4.9 3 10 À4 ) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p ¼ 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.

Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration

“…In conclusion, our results deepen the understanding of the effects of genetic variation at the extended CFH locus and pinpoint a relevant role of FHR proteins in AMD; these results are also supported by a recent study by Unwin et al 62 We describe the involvement of FHR-2 and FHR-5 in AMD and identify low-frequency CFHR2 and CFHR5 variants with a protective effect on AMD. Our study could set a precedent for the analysis of other GWAS loci and pinpoints FHR proteins as potential targets for developing new AMD treatments where individuals with AMD could be selected on the basis of their genetic profile.…”

A proteogenomic signature of age-related macular degeneration in blood

“…CFHR1 and CFHR5 are presumed pathogenic since they impede CFH binding to pro-inflammatory lipid peroxidation products 69 , 70 , and induce inflammasome activation 71 , whereas CFHR1 gene deletion is known to be protective for AMD 69 . Indeed, the two-sample MR test analysis revealed that both proteins were causally linked to AMD, consistent with prior MR analyses of factor H-related proteins found causally related to AMD 37 . However, because their cis regions overlap (Supplementary Data 8 ), from which the genetic instruments are selected, it is impossible to say whether one or both are the causal effector.…”

“…10 ). Significant increases in all factor H-related proteins, including CFHR1, have also been linked to AMD in recent studies 33 , 37 . Figure 7b–d shows scatter plots with the generalized weighted causal estimate and MR-Egger regression for CFHR1, CFHR5, and FUT5, which were all identified as causal candidates in the MR analysis.…”

Local factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration

“…Most reports to date have been inconsistent when measuring systemic FH levels in AMD. For instance, Silva et al [48] and Sharma et al [49] reported reduced levels of FH in AMD cases versus controls, whereas more recent reports with larger patient cohorts failed to detect alternations in systemic FH levels by ELISA due to AMD status [50,51], and no difference in FH levels was found by targeted mass spectrometry [52]. Furthermore, no significant differences have been reported between sera from CFH Y402H genotypes [48].…”