Ultra-rare complement factor 8 coding variants in families with age-related macular degeneration.
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ABSTRACT:
SUBMITTER: Zelinger L
PROVIDER: S-EPMC10156737 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Ultra-rare complement factor 8 coding variants in families with age-related macular degeneration.
Zelinger Lina L Martin Tammy M TM Advani Jayshree J Campello Laura L English Milton A MA Kwong Alan A Weber Claire C Maykoski Jennifer J Sergeev Yuri V YV Fariss Robert R Chew Emily Y EY Klein Michael L ML Swaroop Anand A
iScience 20230403 4
Genome-wide association studies have uncovered 52 independent common and rare variants across 34 genetic loci, which influence susceptibility to age related macular degeneration (AMD). Of the 5 AMD-associated complement genes, complement factor H (CFH) and CFI exhibit a significant rare variant burden implicating a major contribution of the complement pathway to disease pathology. However, the efforts for developing AMD therapy have been challenging as of yet. Here, we report the identification ...[more]
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Project description:Purpose To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Design Prospective, longitudinal study Participants Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Methods Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Main Outcome Measures Progression to AAMD, GA, or NV. Results In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011. Conclusions Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.
| S-EPMC9993025 | biostudies-literature
Project description:Factor I (FI) is a serine protease inhibitor of the complement system. Heterozygous rare genetic variants in complement factor I (CFI) are associated with advanced age-related macular degeneration (AMD). The clinical impact of these variants is unknown since a majority have not been functionally characterized and are classified as 'variants of uncertain significance' (VUS). This study assessed the functional significance of VUS in CFI. Our previous cross-sectional study using a serum-based assay demonstrated that CFI variants in advanced AMD can be categorized into three types. Type 1 variants cause a quantitative deficiency of FI. Type 2 variants demonstrate a qualitative deficiency. However, Type 3 variants consist of VUS that are less dysfunctional than Types 1 and 2 but are not as biologically active as wild type (WT). In this study, we employed site-directed mutagenesis followed by expression of the recombinant variant and a comprehensive set of functional assays to characterize nine Type 3 variants that were identified in 37 individuals. Our studies establish that the expression of the recombinant protein compared with WT is reduced for R202I, Q217H, S221Y and G263V. Further, G362A and N536K, albeit expressed normally, have significantly less cofactor activity. These results led to re-categorization of CFI variants R202I, Q217H, S221Y and G263V as Type 1 variants and to reclassification of N536K and G362A as Type 2. The variants K441R, Q462H and I492L showed no functional defect and remained as Type 3. This study highlights the utility of an in-depth biochemical analysis in defining the pathologic and clinical implications of complement variants underlying AMD.
| S-EPMC9616575 | biostudies-literature
Project description:To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement Factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch's membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common complement Factor H gene (CFH) p.Y402H and age-related maculopathy susceptibility protein 2 gene (ARMS2) p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% confidence interval [CI] -1.66 to -0.37 μm, P = 0.002) and retina (95% CI -5.88 to -0.13 μm, P = 0.04) and a higher AMD risk (odds ratio [OR] = 2.26, 95% CI 1.56 to 3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99) or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI -0.31 to -0.18 μm, P < 0.001 heterozygous; 95% CI -0.62 to -0.42 μm, P < 0.001 homozygous) and retina (95% CI -0.73 to -0.12 μm, P = 0.007 heterozygous; 95% CI -1.08 to -0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele-dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.
| S-EPMC9402241 | biostudies-literature
Project description:Introduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained. Methods: We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes. Results: At a false discovery rate of <0.01, we identified 11 low-frequency AMD variants (minor allele frequency <0.05). Two of those variants were present in the complement C4A gene, including the replacement of the residues that contribute to the Rodgers-1/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 (p = 3.2 × 10-5) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, p = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including C4A, which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen. Conclusion: Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD.
| S-EPMC10859408 | biostudies-literature
Project description:PurposeAge-related macular degeneration (AMD) has a substantial genetic risk component, as evidenced by the risk from common genetic variants uncovered in the first genome-wide association studies. More recently, it has become apparent that rare genetic variants also play an independent role in AMD risk. We sought to determine if rare variants in complement factor H (CFH) played a role in AMD risk.MethodsWe had previously collected DNA from a large population of patients with advanced age-related macular degeneration (A-AMD) and controls for targeted deep sequencing of candidate AMD risk genes. In this analysis, we tested for an increased burden of rare variants in CFH in 1665 cases and 752 controls from this cohort.ResultsWe identified 65 missense, nonsense, or splice-site mutations with a minor allele frequency ≤ 1%. Rare variants with minor allele frequency ≤ 1% (odds ratio [OR] = 1.5, P = 4.4 × 10⁻²), 0.5% (OR = 1.6, P = 2.6 × 10⁻²), and all singletons (OR = 2.3, P = 3.3 × 10⁻²) were enriched in A-AMD cases. Moreover, we observed loss-of-function rare variants (nonsense, splice-site, and loss of a conserved cysteine) in 10 cases and serum levels of FH were decreased in all 5 with an available sample (haploinsufficiency). Further, rare variants in the major functional domains of CFH were increased in cases (OR = 3.2; P = 1.4 × 10⁻³) and the magnitude of the effect correlated with the disruptive nature of the variant, location in an active site, and inversely with minor allele frequency.ConclusionsIn this large A-AMD cohort, rare variants in the CFH gene were enriched and tended to be located in functional sites or led to low serum levels. These data, combined with those indicating a similar, but even more striking, increase in rare variants found in CFI, strongly implicate complement activation in A-AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway.
| S-EPMC4627248 | biostudies-literature
Project description:BACKGROUND/AIMS:Impaired inhibition of the alternative complement pathway by complement factor H (CFH) is linked to age-related macular degeneration (AMD) based on the strong association between CFH variant and AMD. Chlamydia pneumoniae (C pneumoniae) infection can trigger the alternative pathway, but the evidence for an association between C pneumoniae and AMD is contradictory. This study investigated whether C pneumoniae infection is associated with AMD and whether the presence of C pneumonia modulates AMD risk conferred by CFH variants. METHODS:Genomic DNA extracted from peripheral blood of 148 advanced AMD patients and 162 controls was subjected to Taqman and PCR-RFLP for the CFH polymorphism and PCR for the C pneumoniae gene. Genomic DNA was also examined from microdissected macular cells from 59 AMD and 16 age-matched non-AMD archived slides. chi(2) testing was performed for case-control analysis. RESULTS:C pneumoniae infection was associated with increased risk of AMD (OR = 2.17, p<0.017). A CFH variant was also linked to increased risk of AMD (OR = 1.98, p<0.0001). However, no relationship was found between risk-conferring CFH variant and C pneumoniae (OR = 1.81, p = 0.08). CONCLUSION:There is a possible association between AMD and C pneumoniae infection, although CFH may not be directly involved in the pathogenesis of C pneumoniae infection-mediated AMD.
| S-EPMC2746818 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.
| S-EPMC7390936 | biostudies-literature
Project description:Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
| S-EPMC3812337 | biostudies-literature
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.
| S-EPMC4165324 | biostudies-literature
Project description:PurposeTo examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations.MethodsSingle nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay. Plasma CFD was measured by an enzyme-linked immunosorbent assay.ResultsGenetic association was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-analysis of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the association almost confined to females. Copy number variation in the CFD gene was identified in 13 out of 640 samples examined but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concentration was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest versus lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females.ConclusionsCFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic association between a CFD gene SNP and AMD and a significant increase in plasma CFD concentration in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.
| S-EPMC3230905 | biostudies-literature