Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

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Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2 g = 0.42 ± 0.09) and AMD (h2 g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2 g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors

Hypomethylation of the IL17RC promoter in peripheral blood leukocytes is not a hallmark of age-related macular degeneration

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Aberrant DNA methylation within the promoter of IL17RC in peripheral blood mononuclear cells has recently been reported in AMD. To validate this association, we examined DNA methylation of the IL17RC promoter in peripheral blood. First, we used Illumina Human Methylation450 Bead Arrays, a widely accepted platform for measuring global DNA methylation. Second, methylation status at multiple sites within the IL17RC promoter was determined by bisulfite pyrosequencing in two cohorts. Third, a methylation-sensitive quantitative PCR-based assay was performed on a subset of samples. In contrast to previous findings, we did not find evidence of differential methylation between AMD cases and age-matched controls. We conclude that hypomethylation within the IL17RC gene promoter in peripheral blood is not suitable for use as a clinical biomarker of AMD. This study highlights the need for considerable replication of epigenetic association studies prior to clinical application

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Long-term outcome of combined pars plana vitrectomy and scleral fixated sutured posterior chamber intraocular lens implantation

PURPOSE: To investigate the long-term visual outcome and the complication rate following transscleral suture fixation of posterior chamber intraocular lenses (sutured PC-IOLs). DESIGN: A retrospective case-series descriptive study. METHODS: Records of patients who underwent combined pars plana vitrectomy and sutured PC-IOLs at Moorfields Eye Hospital and who had at least 12 months of follow-up were examined for recorded complications. RESULTS: Sixty-one eyes of 48 patients (33 males and 15 females) were identified and included in the analysis, with mean follow-up of 6 years. The mean final best-corrected visual acuity remained at preoperative levels (P=.211) and was largely determined by the underlying ocular pathology before sutured PC-IOL. Overall 30 of 61 (49%) eyes, two or more procedures were performed to reverse a significant peri- or postoperative complication. Breakage of polypropylene sutures was the main indication accounting for 17 of 30 (57%) of those reoperations. Subgroup analysis showed that younger patients were more likely to suffer the above complication (P=.009). The multivariate analysis also showed that longer follow-up was significantly associated with suture breakage (P=.014), with the mean time to breakage approximately 4 years after surgery. CONCLUSIONS: Long-term follow-up of patients undergoing sutured PC-IOLs appears to be associated with a high rate of postoperative complications and significant need for further surgery, which should be discussed during their informed consent process

Anterior capsulotomy integrity after femtosecond laser-assisted cataract surgery

Objective: To compare the incidence of anterior capsular tears after femtosecond laser-assisted cataract surgery (FLACS) versus phacoemulsification cataract surgery (PCS) and to assess the ultrastructural features of anterior capsulotomy specimens (FLACS and PCS) using electron microscopy. Design: Prospective, multicenter, comparative cohort case series. Participants: Consecutive patients undergoing FLACS or PCS. Methods: A prospective cohort study of all patients (n ¼ 1626) undergoing FLACS or PCS by 2 surgeons from centers A and B was undertaken to compare the incidence of anterior capsule tears. Anterior lens capsules were collected by 4 surgeons from centers A, B, C, and D using 3 different commercially available femtosecond platforms, each with latest version upgrades. Lens capsule tissue was prepared for scanning electron microscopy (SEM) using a total of 10 samples for patients undergoing PCS, and 40 samples for patients undergoing FLACS. Main Outcome Measures: Incidence of anterior capsule tear and comparative ultrastructural features of capsular samples from both PCS and FLACS cases. Results: There was a significantly increased rate of anterior capsule tears in the FLACS group (15/804 [1.87%]) when compared with the PCS group (1/822 [0.12%]; P ¼ 0.0002, Fisher exact test). In 7 cases, the anterior capsule tear extended to the posterior capsule. Because all cases had occurred in complete capsulotomy, the integrity of the anterior capsule was questioned in the FLACS group. Subsequent SEM sampling showed irregularity at the capsule margin, as well as multiple apparently misplaced laser pits in normal parts of the tissue. Aberrant pits were approximately 2 to 4 mm apart and occurred at a range of 10 to 100 mm radially from the capsule edge. Conclusions: Laser anterior capsulotomy integrity seems to be compromised by postage-stamp perforations and additional aberrant pulses, possibly because of fixational eye movements. This can lead to an increased rate of anterior capsule tears, and extra care should be taken during surgery after femtosecond laser pretreatment has been performed. A learning curve may account for some of the increased complication rate with FLACS. However, the SEM features raise safety concerns for capsular integrity after FLACS and warrant further investigation

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p −8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches

Predictive factors for treatment outcomes with intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema in clinical practice

Abstract Background Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. Methods This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. Results There was a significant improvement in BCVA (p < 0.001) and CMT (p < 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a < 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive “early functional response” (p < 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p < 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an “early anatomical response”, (p < 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response. Conclusions The study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes. Trial registration The study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 − 067)

An Analysis of Ranibizumab Treatment and Visual Outcomes in Real-World Settings: The Uncover Study

Purpose To describe intravitreal ranibizumab treatment frequency, clinical monitoring, and visual outcomes (including mean central retinal thickness [CRT] and visual acuity [VA] changes from baseline) in neovascular age-related macular degeneration (nAMD) in real-world settings across three ranibizumab reimbursement scenarios in the Middle East, North Africa, and the Asia–Pacific region. Methods Non-interventional multicenter historical cohort study of intravitreal ranibizumab use for nAMD in routine clinical practice between April 2010 and April 2013. Eligible patients were diagnosed with nAMD, received at least one intravitreal ranibizumab injection during the study period, and had been observed for a minimum of 1 year (up to 3 years). Reimbursement scenarios were defined as self-paid, partially-reimbursed, and fully-reimbursed. Results More than three-fourths (n = 2521) of the analysis population was partially-reimbursed for ranibizumab, while 16.4% (n = 532) was fully-reimbursed, and 5.8% was self-paid (n = 188). The average annual ranibizumab injection frequency was 4.1 injections in the partially-reimbursed, 4.7 in the fully-reimbursed and 2.6 in the self-paid populations. The average clinical monitoring frequency was estimated to be 6.7 visits/year, with similar frequencies observed across reimbursement categories. On average, patients experienced VA reduction of −0.7 letters and a decrease in CRT of −44.4 μm. The greatest mean CRT change was observed in the self-paid group, with −92.6 μm. Conclusions UNCOVER included a large, heterogeneous ranibizumab-treated nAMD population in real-world settings. Patients in all reimbursement scenarios attained vision stability on average, indicating control of disease activity. Electronic supplementary material The online version of this article (10.1007/s00417-017-3890-8) contains supplementary material, which is available to authorized users.PubMedWoSScopu

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value &lt; 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.</p