Dataset Information

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 AMD-associated 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 = 2.4 × 10^-10; FHR-2, p = 6.0 × 10^-10; FHR-3, p = 1.5 × 10^-5; FHR-4, p = 1.3 × 10^-3; FHR-5, p = 1.9 × 10^-4) and FHL-1 (p = 4.9 × 10^-4) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 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.

SUBMITTER: Cipriani V

PROVIDER: S-EPMC8387294 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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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.

Cipriani Valentina V Tierney Anna A Griffiths John R JR Zuber Verena V Sergouniotis Panagiotis I PI Yates John R W JRW Moore Anthony T AT Bishop Paul N PN Clark Simon J SJ Unwin Richard D RD

American journal of human genetics 20210713 8

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 AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. ...[more]

PMID: 34260948

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Project description:PurposeThe complement system has been implicated in the pathogenesis of age-related macular degeneration (AMD). Complement factor I (CFI) is a serum protease that inhibits all complement pathways. A previous multicenter study identified a single missense CFI mutation (p.Gly119Arg) in 20/3,567 (0.56%) of AMD cases versus 1/3,937 (0.025%) of controls, thus suggesting that this mutation confers a high risk of AMD. A second CFI mutation, p.Gly188Ala, was identified in one patient with AMD.MethodsWe screened 521 unrelated AMD cases and 627 controls for the p.Gly119Arg and p.Gly188Ala variants. All participants were Caucasian and >55 years, and recruited through Southampton Eye Unit or research clinics in Guernsey. All participants underwent dilated fundal examination by an experienced retinal specialist. SNP assays were performed using KASP™ biochemistry.ResultsThe p.Gly119Arg mutation was identified in 7/521 AMD cases compared to 1/627 age-matched controls (odds ratio [OR] = 8.47, confidence interval [CI] = 1.04-69.00, p = 0.027). There was a varied phenotype among the seven cases with the mutation, which was present in 4/254 (1.6%) cases with active or end-stage wet AMD and 3/267 dry AMD cases (1.1%). The p.Gly188Ala substitution was identified in 1/521 cases and 1/627 controls.ConclusionsOur results identified a much higher frequency of heterozygosity for p.Gly119Arg in both cases and controls than in previous studies. Of note is that our sub-cohort from Guernsey had a particularly high frequency of p.Gly119Arg heterozygosity in affected individuals (4%) compared to our sub-cohort from the mainland (0.71%). Although these data support the conclusions of van de Ven et al. that the p.Gly119Arg substitution confers a high risk of AMD, our data suggest that this missense mutation is not as rare or as highly penetrant as previously reported. There was no difference in frequency for a second CFI variant, p.Gly188Ala, between the cases and the controls.

Project description:PurposeIn genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous GWAS identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore¸ our goal was to investigate ChrX variants for association with AMD.MethodsWe genotyped 29 629 non-Hispanic White (NHW) individuals (M/F:10404/18865; AMD12,087/14723) via a custom chip and imputed after ChrX-specific QC (XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1 221 623 variants on ChrX. Age, informative PCs, and subphenotypes were covariates for logistic association analyses with Fisher's correction. Gene/pathway analyses were performed with VEGAS, GSEASNP, ICSNPathway, DAVID, and mirPath.ResultsLogistic association on NHW individuals with sex correction identified variants in/near the genes SLITRK4, ARHGAP6, FGF13 and DMD associated with AMD (P < 1 × 10-6,Fisher's combined-corrected). Association testing of the subphenotypes of choroidal neovascularization and geographic atrophy (GA), identified variants in DMD associated with GA (P < 1 × 10-6, Fisher's combined-corrected). Via gene-based analysis with VEGAS, several genes were associated with AMD (P < 0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9. Pathway analysis using GSEASNP and DAVID identified genes associated with nervous system development (FDR: P:0.02), and blood coagulation (FDR: P:0.03). Variants in the region of a microRNA (miR) were associated with AMD (P < 0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs showed association with brain disorders and fatty acid elongation (P < 0.05). A long noncoding RNA on ChrX near the DMD locus was also associated with AMD (P = 4 × 10-7). Epistatic analysis (t-statistic) for a quantitative trait of AMD vs control including covariates found a suggestive association in the XG gene (P = 2 × 10^-5).ConclusionsAnalysis of ChrX variation identifies several potential new locifor AMD risk and these variants nominate novel AMD pathways. Further analysis is needed to refine these results and to understand their biological significance and relationship with AMD development in worldwide populations.

Dataset Information

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.

Publications

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.

Similar Datasets

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