Dataset Information

The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

ABSTRACT: To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye.Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Related Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients.There were no statistically significant relationships between clinical findings and genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovascularization (P = 9.0 × 10(-8)), and unilateral late AMD versus bilateral late AMD (P = 5.9 × 10(-8)).In this series, in patients with geographic atrophy or choroidal neovascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S substitution may serve as a marker for bilateral advanced AMD.

SUBMITTER: Schwartz SG

PROVIDER: S-EPMC4269218 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

Schwartz Stephen G SG Agarwal Anita A Kovach Jaclyn L JL Gallins Paul J PJ Cade William W Postel Eric A EA Wang Gaofeng G Ayala-Haedo Juan J Spencer Kylee M KM Haines Jonathan L JL Pericak-Vance Margaret A MA Scott William K WK

Retina (Philadelphia, Pa.) 20120901 8

<h4>Purpose</h4>To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye.<h4>Methods</h4>Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Rel ...[more]

PMID: 22481475

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Project description:PURPOSE: To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. RESULTS: The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects p<0.001) than in PCV (allelic summary OR=2.13 [95% CI, 1.91-2.38], fixed effects p<0.001). The pooled risk allele frequency was significantly higher in neovascular AMD (64.7%) than in PCV (55.6%). The population attributable risks for the variant allele were estimated to be 43.9% (95% CI, 39.0%-48.4%) and 29.7% (95% CI, 25.4%-34.0%) for neovascular AMD and PCV, respectively. No significant between-study heterogeneity was observed in any statistical analysis in this meta-analysis. CONCLUSIONS: Our meta-analysis provides substantial evidence that the ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV. Furthermore, there is compelling evidence that the risk attributable to the A69S variant differs between geographic atrophy and neovascular AMD. Together with defining the molecular basis of susceptibility, understanding the relationships between this genomic region and disease subtypes will yield important insights, elucidating the biologic architecture of this phenotypically heterogeneous disorder.

Project description:PurposeTo examine the association between sequence variants in genetic risk factors for age-related macular degeneration (AMD) and delayed rod-mediated dark adaptation (RMDA), the first functional biomarker for incident AMD, in older adults with normal macular health and early AMD.DesignCross-sectional.ParticipantsAdults 60 years of age or older showing normal macular health (defined as both eyes at step 1 on the Age-Related Eye Disease Study 9-step AMD classification system) and those with AMD in one or both eyes (defined as steps 2-9).MethodsSingle nucleotide polymorphisms were genotyped in the complement factor H (CFH) and ARMS2 genes using a Taqman assay. Rod-mediated dark adaptation was assessed in 1 eye after photobleach with targets centered at 5° on the inferior vertical meridian. Rate of dark adaptation was defined by rod intercept time (RIT), duration (in minutes) required for sensitivity to reach a criterion sensitivity level in the latter half of the second component of rod recovery. Associations between CFH and ARMS2 polymorphisms and RMDA were adjusted for age and smoking.Main outcome measureRod intercept time.ResultsThe sample consisted of 543 participants having both genotype and RIT determination; 408 showed normal macular health and 135 demonstrated AMD, most having early AMD (124 of 135). For the combined sample, higher RIT (slower RMDA) was observed for both the A69S variant in ARMS2 and the Y402H variant in CFH (adjusted P = 0.0001 and P = 0.0023, respectively). For healthy participants, the A69S variant in ARMS2 was associated with higher RIT (adjusted P = 0.0011), whereas the Y402H variant in CFH was not (adjusted P = 0.2175). For AMD patients, the A69S variant of ARMS2 and the Y402H variant of CFH were associated with higher RIT (adjusted P = 0.0182 and P = 0.0222, respectively). Those with a larger number of high-risk ARMS2 and CFH alleles showed higher RIT, in both healthy and AMD groups (adjusted P = 0.0002 and P < 0.0001, respectively).ConclusionsWe report a novel association wherein older adults with high-risk ARMS2 and CFH genotypes are more likely to demonstrate delayed RMDA, the first functional biomarker for incident early AMD. Before the AMD clinical phenotype is present, those showing normal macular health with the ARMS2 A69S allele demonstrate delayed RMDA. Understanding ARMS2 function is a research priority.

Project description:BackgroundAge-related macular degeneration (AMD) is a common disease causing visual impairment and blindness. Various gene variants are strongly associated with late stage AMD, but little is known about the genetics of early forms of the disease. This study evaluated associations of genetic factors and different AMD stages depending on unilateral and bilateral disease severity.MethodsIn this case-control study, participants were assigned to nine AMD severity stages based on the characteristics of each eye. 18 single nucleotide polymorphisms (SNPs) were genotyped and attempted to correlate with AMD severity stages by uni- and multivariate logistic regression analyses and trend analyses. Area under the receiver operating characteristic curves (AUC) were calculated.ResultsOf 3444 individuals 1673 were controls, 379 had early AMD, 333 had intermediate AMD and 989 showed late AMD stages. With increasing severity of disease and bilateralism more SNPs with significant associations were found. Odds ratios, especially for the main risk polymorphisms in ARMS2 (rs10490924) and CFH (rs1061170), gained with increasing disease severity and bilateralism (exemplarily: rs1061170: unilateral early AMD: OR = 1.18; bilateral early AMD: OR = 1.20; unilateral intermediate AMD: OR = 1.28; bilateral intermediate AMD: OR = 1.39, unilateral geographic atrophy (GA): OR = 1.50; bilateral GA: OR = 1.71). Trend analyses showed p<0.0001 for ARMS2 (rs10490924) and for CFH (rs1061170), respectively. AUC of risk models for various AMD severity stages was lowest for unilateral early AMD (AUC = 0.629) and showed higher values in more severely and bilaterally affected individuals being highest for late AMD with GA in one eye and neovascular AMD in the other eye (AUC = 0.957).ConclusionThe association of known genetic risk factors with AMD became stronger with increasing disease severity, which also led to an increasing discriminative ability of AMD cases and controls. Genetic predisposition was also associated with the disease severity of the fellow-eye, highlighting the importance of both eyes in AMD patients.

Dataset Information

The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

Publications

The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

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