E. Souied

Common Variants near FRK/COL10A1 and VEGFA are Associated with Advanced Age-related Macular Degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-Related Macular Degeneration Subtypes

PURPOSE To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

Treatment of wet age-related macular degeneration by ranibizumab in “real life” in France: treatment behaviours and associated visual outcome

noted in any of the included eyes. Mean CFT before TA injection, 1 month and 3 months after TA injection, was 482.2 125.1 lm, 300.8 122.8 lmand343.0 131.6 lm, respectively. CFT differed significantly among the three time-points (p < 0.001). CFT before TA injection was significantly different from that measured at 1 and 3 monthsafter intravitrealTA(p = 0.001 and p = 0.005, respectively). CFT ≤250 lm was achieved in eight eyes (40.0%) and six eyes (30.0%) at 1 and 3 months afterTA injection, respectively. In four eyes (20.0%), intraocular pressure increased to levels >21 mmHg. These eyes were successfully treated with topical antiglaucoma medication. Mild cataract progression was noted in one of eight phakic eyes. Intravitreal TA is an effective treatment modality for DME (Jonas et al. 2003; Audren et al. 2006). TA suppresses VEGF as well as other cytokines, whereas the effects of antiVEGF therapies are primarily associated with VEGF (Shimura et al. 2008; Sohn et al. 2011). This difference in the mechanism of action of each treatment modality suggests that some antiVEGF-resistant DMEs may benefit from TA therapy. Although the potential role of intravitreal TA in this condition has been suggested (Thomas et al. 2013), the efficacy of intravitreal TA in anti-VEGF-resistant DME has not yet been analysed in a case series. In our small case series, significant improvements in BCVA as well as significant decreases in CFT were noted 1 month after intravitreal TA injection in eyes with bevacizumab-resistant DME. However, increases in CFT and deteriorations in BCVA were noted in some eyes between 1 and 3 months after TA injection. As a result, BCVA at 3 months after TA injection was not significantly different when compared with the values measured before TA injection. Although the overall improvement in visual acuity was limited, BCVA improvements of ≥2 lines weremaintained up to 3 months in 15% of the eyes. This result suggests that intravitreal TA has a valid short-term effect in some patients with DME that is resistant to bevacizumab. Considering the mean number of anti-VEGF injections before TA injection was only 2.4, it is possible that our results may not be valid for DMEs resistant to a greater number of anti-VEGF injections. Further studies investigating the efficacy of repeated TA injections or combined anti-VEGF plus TA treatment may help to establish the optimal treatment strategy in this condition.