Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.
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SUBMITTER: Zhan X
PROVIDER: S-EPMC3812337 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
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Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.
Zhan Xiaowei X Larson David E DE Wang Chaolong C Koboldt Daniel C DC Sergeev Yuri V YV Fulton Robert S RS Fulton Lucinda L LL Fronick Catrina C CC Branham Kari E KE Bragg-Gresham Jennifer J Jun Goo G Hu Youna Y Kang Hyun Min HM Liu Dajiang D Othman Mohammad M Brooks Matthew M Ratnapriya Rinki R Boleda Alexis A Grassmann Felix F von Strachwitz Claudia C Olson Lana M LM Buitendijk Gabriëlle H S GH Hofman Albert A van Duijn Cornelia M CM Cipriani Valentina V Moore Anthony T AT Shahid Humma H Jiang Yingda Y Conley Yvette P YP Morgan Denise J DJ Kim Ivana K IK Johnson Matthew P MP Cantsilieris Stuart S Richardson Andrea J AJ Guymer Robyn H RH Luo Hongrong H Ouyang Hong H Licht Christoph C Pluthero Fred G FG Zhang Mindy M MM Zhang Kang K Baird Paul N PN Blangero John J Klein Michael L ML Farrer Lindsay A LA DeAngelis Margaret M MM Weeks Daniel E DE Gorin Michael B MB Yates John R W JR Klaver Caroline C W CC Pericak-Vance Margaret A MA Haines Jonathan L JL Weber Bernhard H F BH Wilson Richard K RK Heckenlively John R JR Chew Emily Y EY Stambolian Dwight D Mardis Elaine R ER Swaroop Anand A Abecasis Goncalo R GR
Nature genetics 20130915 11
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 descr ...[more]
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Project description:ImportanceThe complement factor H R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset; however, its associated phenotype has not been well characterized.ObjectiveTo describe specific fundus features of a white population with the R1210C rare variant.Design, setting, and participantsFundus features specific for diagnosis and disease staging were retrospectively characterized by systematic review of all available fundus images for each patient, including color photography, fluorescein angiography, fundus autofluorescence, and optical coherence tomography, at a tertiary ophthalmologic referral center. For this retrospective observational study conducted from 2012 to 2014, enrolled patients with the variant and their family members without the variant were identified from the Age-Related Macular Degeneration Study for a family-based study arm. For patients with the variant but without a family member enrolled in the study, age-matched comparison individuals without the variant were selected randomly from the database.Main outcomes and measuresThe presence of drusen in the macula (macular drusen score) and estimated number (total macular drusen score) were assessed. The presence of drusen in the extramacular regions (extramacular drusen score), pigmentary abnormalities, and disease staging were also evaluated. Binary logistic regression models were used to evaluate the association between rare variant status and ocular phenotypes.ResultsImages from a total of 143 patients (283 eyes), including 62 patients with the rare variant, were analyzed. Drusen score covariates were associated with the R1210C rare variant. A larger proportion of patients carrying the variant had the highest level of macular and total macular drusen scores compared with those without the variant (57.9% vs 16.7% and 52.9% vs 14.2%, respectively; P for trend < .001 for both scores). Patients carrying the rare variant had a much greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; P < .001). A higher prevalence of geographic atrophy was observed among patients carrying the variant (odds ratio, 13.7; 95% CI, 5.0-37.7; P < .001).Conclusions and relevanceThe typical phenotype of the complement factor H R1210C rare variant is associated with extensive drusen accumulation in the macula and throughout the fundus, as well as with a high risk for having advanced disease. Better characterization of genetic profiles in age-related macular degeneration may be important for screening and future therapeutic strategies for this vision-threatening condition.
| S-EPMC6516461 | biostudies-literature
Project description:PurposeGenetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated.MethodsWe performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs.ResultsWe identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues.ConclusionsIn total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.
| S-EPMC9363678 | 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: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:BackgroundGiven the relatively high prevalence of age-related macular degeneration (AMD) and the increased incidence of AMD as populations age, the results of trials of novel treatments are awaited with much anticipation. The complement cascade describes a series of proteolytic reactions occurring throughout the body that generate proteins with a variety of roles including the initiation and promotion of immune reactions against foreign materials or micro-organisms. The complement cascade is normally tightly regulated, but much evidence implicates complement overactivity in AMD and so it is a logical therapeutic target in the treatment of AMD.ObjectivesTo assess the effects and safety of complement inhibitors in the prevention or treatment of advanced AMD.Search methodsWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2013), EMBASE (January 1980 to November 2013), Allied and Complementary Medicine Database (AMED) (January 1985 to November 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1990 to November 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 November 2013. We also performed handsearching of proceedings, from 2012 onwards, of meetings and conferences of specific professional organisations.Selection criteriaWe planned to include randomised controlled trials (RCTs) with parallel treatment groups which investigated either the prevention or treatment of advanced AMD by inhibition of the complement cascade.Data collection and analysisTwo authors (MW and GMcK) independently evaluated all the titles and abstracts resulting from the searches. We contacted companies running clinical trials which had not yet reported results to request information. Since no trials met our inclusion criteria, we undertook no assessment of quality or meta-analysis.Main resultsWe identified and screened 317 references but there were no published RCTs that met the inclusion criteria. We identified two ongoing studies: one phase I study and one phase II study.Authors' conclusionsThere is insufficient information at present to generate evidence-based recommendations on the potential safety and efficacy of complement inhibitors for prevention or treatment of AMD. However we anticipate the results of ongoing trials.
| S-EPMC6885067 | biostudies-literature
Project description:ImportanceRare variants in the complement factor H (CFH) gene and their association with age-related macular degeneration (AMD) have been described. However, there is limited literature on the phenotypes accompanying these rare variants. Phenotypical characteristics could help ophthalmologists select patients for additional genetic testing.ObjectiveTo describe the phenotypical characteristics of patients with AMD carrying a rare variant in the CFH gene.Design, setting, and participantsIn this cross-sectional study, we searched the genetic database of the department of ophthalmology at the Radboudumc (tertiary ophthalmologic referral center) and the European Genetic Database for patients with AMD with a rare genetic variant in the CFH gene. Patient recruitment took place from March 30, 2006, to February 18, 2013, and data were analyzed from November 30, 2015, to May 8, 2017. Phenotypical features on fundus photographs of both eyes of patients were graded by 2 independent reading center graders masked for carrier status.Main outcomes and measuresDifferences in phenotypical characteristics between rare variant carriers and noncarriers were analyzed using univariable generalized estimated equations logistic regression models accounting for intereye correlation.ResultsAnalyses included 100 eyes of 51 patients with AMD carrying a CFH variant (mean [SD] age, 66.7 [12.1] years; 64.7% female) and 204 eyes of 102 age-matched noncarriers (mean [SD] age, 67.1 [11.8] years; 54.9% female). Carrying a rare pathogenic CFH variant was associated with larger drusen area (odds ratio range, 6.98 [95% CI, 2.04-23.89] to 18.50 [95% CI, 2.19-155.99]; P = .002), presence of drusen with crystalline appearance (odds ratio, 3.24; 95% CI, 1.24-8.50; P = .02), and drusen nasal to the optic disc (odds ratio range, 4.03 [95% CI, 1.70-9.56] to 7.42 [95% CI, 0.65-84.84]; P = .003).Conclusions and relevanceIdentification of rare CFH variant carriers may be important for upcoming complement-inhibiting therapies. Patients with an extensive drusen area, drusen with crystalline appearance, and drusen nasal to the optic disc are more likely to have a rare variant in the CFH gene. However, it is not likely that carriers can be discriminated from noncarriers based solely on phenotypical characteristics from color fundus images. Therefore, ophthalmologists should consider genetic testing in patients with these phenotypic characteristics in combination with other patient characteristics, such as early onset, cuticular drusen on fluorescein angiography, and family history of AMD.
| S-EPMC5710490 | 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: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:In the age-related macular degeneration (AMD) 'inflammation model', local inflammation plus complement activation contributes to the pathogenesis and progression of the disease. Multiple genetic associations have now been established correlating the risk of development or progression of AMD. Stratifying patients by their AMD genetic profile may facilitate future AMD therapeutic trials resulting in meaningful clinical trial end points with smaller sample sizes and study duration.
| S-EPMC4709545 | biostudies-literature
Project description:PURPOSE:To 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. METHODS:Single 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. RESULTS:Genetic 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. CONCLUSIONS:CFD 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