Genotypic Influences on Severity of Exudative Age-Related Macular Degeneration

Leveziel, Nicolas; Puche, Nathalie; Richard, Florence; Somner, John; Zerbib, Jennyfer; Bastuji‐Garin, Sylvie; Cohen, Salomon Y.; Korobelnik, Jean‐François; Sahel, José‐Alain; Soubrane, G.; Benlian, Pascale; Souied, Eric H.

doi:10.1167/iovs.09-4423

Cited by 30 publications

(32 citation statements)

References 49 publications

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“…However, most of these studies have produced variable results; for example, the Y402H variant in the CFH gene has been associated with poor VA outcome in some studies but in other studies has been reported to show no association with VA. Similarly, inconsistent results of association were reported for ARMS2/HTRA1 1127. Our pooled GWAS findings did not identify genome-wide significance for SNPs in the previously associated known AMD risk genes CFH, VEGF-A, HTRA1/ARMS2 (Supplementary Table S5).…”

Section: Discussioncontrasting

confidence: 67%

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

Riaz

Lorés‐Motta

Richardson

et al. 2016

Sci Rep

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Pooled DNA based GWAS to determine genetic association of SNPs with visual acuity (VA) outcome in anti-vascular endothelial growth factor (anti-VEGF) treated neovascular age-related macular degeneration (nAMD) patients. We performed pooled DNA based GWAS on 285 anti-VEGF treated nAMD patients using high density Illumina 4.3 M array. Primary outcome was change in VA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters after 6 months of anti-VEGF treatment (patients who lost ≥5 ETDRS letters classified as non-responders and all remaining classified as responders). GWAS analysis identified 44 SNPs of interest: 37 with strong evidence of association (p < 9 × 10−8), 2 in drug resistance genes (p < 5 × 10−6) and 5 nonsynonymous changes (p < 1 × 10−4). In the validation phase, individual genotyping of 44 variants showed three SNPs (rs4910623 p = 5.6 × 10−5, rs323085 p = 6.5 × 10−4 and rs10198937 p = 1.30 × 10−3) remained associated with VA response at 6 months. SNP rs4910623 also associated with treatment response at 3 months (p = 1.5 × 10−3). Replication of these three SNPs in 376 patients revealed association of rs4910623 with poor VA response after 3 and 6 months of treatment (p = 2.4 × 10−3 and p = 3.5 × 10−2, respectively). Meta-analysis of both cohorts (673 samples) confirmed association of rs4910623 with poor VA response after 3 months (p = 1.2 × 10−5) and 6 months (p = 9.3 × 10−6) of treatment in nAMD patients.

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Section: Discussioncontrasting

confidence: 67%

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

Riaz

Lorés‐Motta

Richardson

et al. 2016

Sci Rep

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“…32 One series reported that ARMS2 , but not CFH , C2 , C3 , APOE , or TLR3 , was associated with progression of GA calculated from serial fundus photographs, but not with secondary measures of GA progression. 33 Another series reported that ARMS2 , CFH , and C3 are associated with the presence, but not the progression, of GA. 34 …”

Section: Discussionmentioning

confidence: 99%

The Arms2 A69s Variant and Bilateral Advanced Age-Related Macular Degeneration

Schwartz

Agarwal

Kovach

et al. 2012

Retina

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Purpose 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. Methods 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. Results 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). Conclusion 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.

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“…However, so far no genetic association with late stage AMD was observed for any genes associated with these signaling pathways. In this context, it should be noted that until now only few studies evaluated a genetic association for progression and severity of AMD [18], [19]. These studies mainly focused on strong (and known) signals associated with increased risk for AMD and therefore may have missed possible existing associations.…”

Section: Discussionmentioning

confidence: 99%

A Circulating MicroRNA Profile Is Associated with Late-Stage Neovascular Age-Related Macular Degeneration

et al. 2014

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Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in Western populations over 55 years. A growing number of gene variants have been identified which are strongly associated with an altered risk to develop AMD. Nevertheless, gene-based biomarkers which could be dysregulated at defined stages of AMD may point toward key processes in disease mechanism and thus may support efforts to design novel treatment regimens for this blinding disorder. Circulating microRNAs (cmiRNAs) which are carried by nanosized exosomes or microvesicles in blood plasma or serum, have been recognized as valuable indicators for various age-related diseases. We therefore aimed to elucidate the role of cmiRNAs in AMD by genome-wide miRNA expression profiling and replication analyses in 147 controls and 129 neovascular AMD patients. We identified three microRNAs differentially secreted in neovascular (NV) AMD (hsa-mir-301-3p, pcorrected = 5.6*10−5, hsa-mir-361-5p, pcorrected = 8.0*10−4 and hsa-mir-424-5p, pcorrected = 9.6*10−3). A combined profile of the three miRNAs revealed an area under the curve (AUC) value of 0.727 and was highly associated with NV AMD (p = 1.2*10−8). To evaluate subtype-specificity, an additional 59 AMD cases with pure unilateral or bilateral geographic atrophy (GA) were analyzed for microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p. While we found no significant differences between GA AMD and controls neither individually nor for a combined microRNAs profile, hsa-mir-424-5p levels remained significantly higher in GA AMD when compared to NV (pcorrected<0.005). Pathway enrichment analysis on genes predicted to be regulated by microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p, suggests canonical TGFβ, mTOR and related pathways to be involved in NV AMD. In addition, knockdown of hsa-mir-361-5p resulted in increased neovascularization in an in vitro angiogenesis assay.

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Genotypic Influences on Severity of Exudative Age-Related Macular Degeneration

Abstract: This study demonstrates an association between the at-risk allele of the ARMS2/LOC387715 locus and classic CNV, fibrovascular lesions, and poor VA. Individuals double homozygous for both at-risk alleles had a higher risk of being affected with a severe form of AMD at an earlier age.

Cited by 30 publications

References 49 publications

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

The Arms2 A69s Variant and Bilateral Advanced Age-Related Macular Degeneration

A Circulating MicroRNA Profile Is Associated with Late-Stage Neovascular Age-Related Macular Degeneration

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