Dataset Information

Complement factor H Val62Ile variant and risk of age-related macular degeneration: a meta-analysis.

ABSTRACT: PURPOSE: To evaluate the precise association of complement factor H (CFH) Val62Ile polymorphism with age-related macular degeneration (AMD) susceptibility. METHODS: We performed a meta-analysis using databases including PubMed, EMBASE, and Web of Science to find relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed-effect and random-effects models. The inconsistency index (I(2)) was used to assess heterogeneity. Funnel plots and Egger's test were used to evaluate publication bias. Sensitivity analysis was also performed. RESULTS: Fourteen studies including 4,438 patients with AMD and 6,099 controls based on the search criteria were involved in the meta-analysis. In overall populations, the pooled OR(1) for genotype GA+GG versus homozygous genotype AA was 2.28 (95% confidence interval (CI): 1.48-3.52), the OR(2) of heterozygous genotype GA versus AA was 1.58 (95% CI: 1.13-2.19), the OR(3) of homozygous genotype GG versus AA was 2.90 (95% CI: 1.95-4.30), and the OR(4) of allele G versus A was 1.77 (95% CI: 1.43-2.21). In Asian populations, our results provided substantial evidence that the Val62Ile variant was significantly associated with AMD (OR(4) = 1.85, 95% CI: 1.63-2.09). However, in Caucasian populations, no significant association of Val62Ile with AMD was established in all circumstances. CONCLUSIONS: Our analysis provides substantial evidence that the Val62Ile variant is significantly associated with AMD in Asian populations. However, our results have demonstrated no link between the Val62Ile polymorphism and AMD in Caucasian populations.

SUBMITTER: Yuan D

PROVIDER: S-EPMC3580987 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Complement factor H Val62Ile variant and risk of age-related macular degeneration: a meta-analysis.

Yuan Dongqing D Yang Qin Q Liu Xiaoyi X Yuan Donglan D Yuan Songtao S Xie Ping P Liu Qinghuai Q

Molecular vision 20130213

<h4>Purpose</h4>To evaluate the precise association of complement factor H (CFH) Val62Ile polymorphism with age-related macular degeneration (AMD) susceptibility.<h4>Methods</h4>We performed a meta-analysis using databases including PubMed, EMBASE, and Web of Science to find relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed-effect and random-effects models. The inconsistency index (I(2)) was used to assess heterogeneity. Funnel plots and Eg ...[more]

PMID: 23441108

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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: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.

Dataset Information

Complement factor H Val62Ile variant and risk of age-related macular degeneration: a meta-analysis.

Publications

Complement factor H Val62Ile variant and risk of age-related macular degeneration: a meta-analysis.

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