Evaluation of serum sphingolipids and the influence of genetic risk factors in age-related macular degeneration

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Alterations in pathogen-specific cellular and humoral immunity associated with acute peripheral facial palsy of infectious origin

Background Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difcult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specifc T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin. Methods In this observational study, pathogen-specifc T cells were quantifed in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for diferentiation (CD27) and proliferation (Ki67). Pathogen-specifc antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics. Results Patients with PFP were more often HSV-seropositive than controls (p=0.0003), whereas VZV- and borreliaspecifc antibodies did not difer between groups. Although the quantity and general phenotypical characteristics of antigen-specifc T cells did not difer either, expression of CTLA-4 and Ki67 was highly increased in VZV-specifc T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67- expression profle of borrelia-specifc T cells was also found in a patient with acute neuroborreliosis. Discussion In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specifc T cell characteristics seem insufcient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specifc T cell phenotype and function may allow identifcation of VZV- and borrelia-triggered PFPs. If confrmed in larger studies, antigen-specifc immune-phenotyping may have the potential to improve specifcity of the clinical diagnosis

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

A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined PADJ = 1.15 × 10−6, OR 1.332 (1.187–1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10−8, OR 1.541 (1.324–1.796); males: PADJ = 0.382, OR 1.084 (0.905–1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis

Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane

Purpose: Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. Design: Genome-wide case-control association study of WES data. Participants: One thousand one hundred twenty-five AMD patients and 1361 control participants. Methods: A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. Main Outcome Measures: Genetic variants associated with AMD. Results: We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [

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

Retinal Detachment Part 2 Treatment Strategies

Zusammenfassung Dieser Beitrag beschaftigt sich mit der Behandlung der Netzhautablosung. Hier wird unterschieden zwischen behandlungsbedurftigen Ablatiovorstufen, die retinopexiert werden, und der manifesten Netzhautablosung, welche weiterfuhrender Chirurgie bedarf. Nicht immer bedeutet ein anatomischer Erfolg zugleich auch einen funktionellen Erfolg. Typische postoperative Komplikationen und Einflussfaktoren auf das anatomische und funktionelle Ergebnis werden vorgestellt und diskutiert. Abstract This review article summarizes the relevant surgical strategies for retinal detachment repair and discusses common postoperative complications, as well as factors influencing the functional and anatomical results. Treatment of retinal detachment requires surgery. In most cases, pars plana vitrectomy is performed. In phakic patients with a clear lens scleral buckling can be considered as an alternative. Laser and cryotherapy are still the standard for treatment in symptomatic retinal tears or degenerations without retinal detachment. Postoperatively, the occurrence of a re-detachment as well as the development of proliferative vitreoretinopathy can have a negative influence on postoperative results. Furthermore, typical complications include the occurrence of a cystoid macular edema, epiretinal membrane or even persistent neurosensory detachment. Functional results are significantly influenced by macular involvement and the primary anatomical success rate

Retinal Detachment Part 1 Epidemiology, Risk Factors, Clinical Characteristics, Diagnostic Approach

Zusammenfassung Dieser Beitrag beinhaltet eine ubersicht uber die Epidemiologie, die Risikofaktoren und das klinische Bild sowie die Diagnostik der rhegmatogenen (rissbedingten) Netzhautablosung. Diese ist von einer Retinoschisis sowie den traktiven und exsudativen Formen der Netzhautablosung hinsichtlich ihrer Haufigkeit, den Risikofaktoren, ihrer Entstehung und dem klinischen Bild zu unterscheiden. Abstract This review article gives an overview of the epidemiology, relevant risk factors, clinical characteristics and the diagnostic approach of rhegmatogenous retinal detachment. Rhegmatogenous retinal detachment is an ophthalmologic emergency needing immediate surgical treatment. Main risk factors are retinal tears, myopia and previous cataract surgery. For patients with symptoms of posterior vitreous detachment, indirect ophthalmoscopy under pupil dilatation is necessary to diagnose retinal tears or retinal detachment. Differential diagnoses are tractive or exudative forms of retinal detachment or retinoschisis