Dataset Information

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

ABSTRACT: BACKGROUND:Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS:To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. RESULTS:In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION:The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

SUBMITTER: Sofat R

PROVIDER: S-EPMC3304526 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

Sofat Reecha R Casas Juan P JP Webster Andrew R AR Bird Alan C AC Mann Samantha S SS Yates John R W JR Moore Anthony T AT Sepp Tiina T Cipriani Valentina V Bunce Catey C Khan Jane C JC Shahid Humma H Swaroop Anand A Abecasis Gonçalo G Branham Kari E H KE Zareparsi Sepideh S Bergen Arthur A AA Klaver Caroline C W CC Baas Dominique C DC Zhang Kang K Chen Yuhong Y Gibbs Daniel D Weber Bernhard H F BH Keilhauer Claudia N CN Fritsche Lars G LG Lotery Andrew A Cree Angela J AJ Griffiths Helen L HL Bhattacharya Shomi S SS Chen Li L LL Jenkins Sharon A SA Peto Tunde T Lathrop Mark M Leveillard Thierry T Gorin Michael B MB Weeks Daniel E DE Ortube Maria Carolina MC Ferrell Robert E RE Jakobsdottir Johanna J Conley Yvette P YP Rahu Mati M Seland Johan H JH Soubrane Gisele G Topouzis Fotis F Vioque Jesus J Tomazzoli Laura L Young Ian I Whittaker John J Chakravarthy Usha U de Jong Paulus T V M PT Smeeth Liam L Fletcher Astrid A Hingorani Aroon D AD

International journal of epidemiology 20120113 1

<h4>Background</h4>Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.<h4>Methods</h4>To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with diffe ...[more]

PMID: 22253316

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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: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.

Project description:BACKGROUND:Given 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. OBJECTIVES:To assess the effects and safety of complement inhibitors in the prevention or treatment of advanced AMD. SEARCH METHODS:We 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 CRITERIA:We 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 ANALYSIS:Two 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 RESULTS:We 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' CONCLUSIONS:There 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.

Dataset Information

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

Publications

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

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