Differences in the Surgical Outcomes of Glaucoma Surgery in Patients of African Caribbean Descent.

PURPOSE: People of African Caribbean Descent (ACD) have a higher prevalence of glaucoma compared to people of European Descent (ED) and there is uncertainty if treatment outcomes are equivalent between the two groups. To assess surgical failure rates comparing ACD with ED focusing on trabeculectomy, aqueous shunt implantation, non-penetrating filtering surgery (NPFS), and minimally invasive glaucoma surgery (MIGS) by performing a systematic review in accordance with the PRISMA guidelines and to determine whether there is any evidence in to show a difference in success rates based on race. METHODS: A systematic review of articles using the CENTRAL, Ovid MEDLINE, PubMed, EMBASE, and ClinicalTrials.gov databases was completed. Additional studies were identified by contacting clinical experts and searching bibliographies. All retrospective and prospective studies on trabeculectomy, aqueous shunt implantation, NPFS, and MIGS that included at least 20% ACD were included. Two review authors independently screened search results for eligibility and inclusion and extracted the data using pre-determined fields. RESULTS: A total of 76 studies were identified for inclusion in the review. Glaucoma surgical outcomes in ACD appear to be poorer compared to ED overall, particularly for trabeculectomy. Data on NPFS are limited, but the studies completed thus far demonstrate surprisingly good results for ACD, particularly when compared to ED, who have significantly lower pre-operative IOPs. Evidence from studies investigating aqueous shunts does not suggest that ACD have poorer outcomes than ED. There is not enough data on MIGS to provide a significant conclusion. CONCLUSION: In a population where trabeculectomy may no longer be the gold standard, sufficiently powered studies assessing surgical outcomes in aqueous shunts, NPFS, and MIGS are needed to guide clinicians.

A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS: Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS: Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES: Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.

A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population.

BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10-5 ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

Prevalence of vitreomacular interface abnormalities on spectral domain optical coherence tomography of patients undergoing macular photocoagulation for centre involving diabetic macular oedema.

AIM: Macular traction may influence the formation and response to treatment of diabetic macular oedema (DME). The aim of this study was to determine the prevalence and associations of spectral domain optical coherence tomography (SD-OCT) evident epiretinal membrane (ERM) and/or partial vitreomacular separation (pVMS) in consecutive patients undergoing macular photocoagulation for centre involving DME. METHODS: A single-centre retrospective cross-sectional observational study. RESULTS: 198 eyes of 198 patients were included. Twelve per cent of eyes demonstrated pVMS and 14% ERM. All cases of pVMS had vitreoretinal adhesion located in the Early Treatment Diabetic Retinopathy Study grid central 1 mm subfield. In 2/3 of ERM cases, ERM was either found in the central subfield or the thickening associated with ERM was contiguous with the thickening in the central subfield. Patients with signs of ERM or pVMS were significantly older and had significantly worse acuity than those without (mean age 67.2 vs 62.8 years (p=0.02); 0.49 vs 0.31 logMAR, p=0.0006). Macular thickness was similar in both groups. The prevalence of pVMS and/or ERM were 31% in Caucasian, 5% in Asian and 24% in Afro-Caribbean subjects (p=0.11). CONCLUSIONS: ERM or pVMS was found on SD-OCT scanning in 25% of patients undergoing laser for centre involving DME. In 20% of all patients, these potentially tractional elements were either present in the central subfield scan or the traction was contiguous with the central macular thickening, suggesting a possible role for surgical or enzymatic relief of traction in their management. This requires targeted investigation.

Gradient Boosting as a SNP Filter: an Evaluation Using Simulated and Hair Morphology Data.

Typically, genome-wide association studies consist of regressing the phenotype on each SNP separately using an additive genetic model. Although statistical models for recessive, dominant, SNP-SNP, or SNP-environment interactions exist, the testing burden makes an evaluation of all possible effects impractical for genome-wide data. We advocate a two-step approach where the first step consists of a filter that is sensitive to different types of SNP main and interactions effects. The aim is to substantially reduce the number of SNPs such that more specific modeling becomes feasible in a second step. We provide an evaluation of a statistical learning method called "gradient boosting machine" (GBM) that can be used as a filter. GBM does not require an a priori specification of a genetic model, and permits inclusion of large numbers of covariates. GBM can therefore be used to explore multiple GxE interactions, which would not be feasible within the parametric framework used in GWAS. We show in a simulation that GBM performs well even under conditions favorable to the standard additive regression model commonly used in GWAS, and is sensitive to the detection of interaction effects even if one of the interacting variables has a zero main effect. The latter would not be detected in GWAS. Our evaluation is accompanied by an analysis of empirical data concerning hair morphology. We estimate the phenotypic variance explained by increasing numbers of highest ranked SNPs, and show that it is sufficient to select 10K-20K SNPs in the first step of a two-step approach.

Validation of printed and computerised crowded Kay picture logMAR tests against gold standard ETDRS acuity test chart measurements in adult and amblyopic paediatric subjects.

AIMS: The impression exists that picture acuity scores may overestimate function when subjects are switched to letter charts. This has not been systematically investigated. The aims of this study were to validate both printed crowded Kay picture (pCKP) and computerised CKP (cCKP) logMAR test acuity measurements against gold standard ETDRS letter chart scores. METHODS: A total of 30 adult subjects with various ophthalmic disease and 40 amblyopic children underwent test and re-test visual acuity measurements using the ETDRS chart, the pCKP logMAR test, and the cCKP acuity scores taken, using the COMPlog visual acuity measurement system. Bland and Altman methods were employed. RESULTS: Computerised and printed Kay picture acuity scores agreed well. Both Kay picture test measurements were systematically biased when compared with ETDRS chart measurements. No significant proportional bias was found. The test retest variability (TRV) of all three tests was found to be similar between ± 0.14 and 0.16 logMAR in both groups. CONCLUSIONS: All three tests were similarly replicable and computerised Kay pictures appear to be a valid alternative to hard copy Kay pictures. Kay picture acuity measurements were systematically biased when compared with the gold standard ETDRS. Measurement error means that differences of up to 0.16 logMAR may be observed in clinically stable patients when re-measured using the same technique. A combination of TRV and systematic bias can however lead to differences of up to 0.40 logMAR in stable amblyopic patients when switched from CKPs to ETDRS chart acuity measurements.

Sequencing of the CHST6 gene in Czech macular corneal dystrophy patients supports the evidence of a founder mutation.

AIMS: To characterise the role of the carbohydrate sulfotransferase gene (CHST6) in macular corneal dystrophy (MCD) in Czech patients. METHODS: The coding region of the CHST6 gene was directly sequenced in 10 affected and five unaffected members from eight apparently unrelated MCD families. The type of MCD was determined by enzyme-linked immunosorbent assay of antigenic keratan sulfate (KS) in serum and by immunohistochemical staining of corneas with monoclonal anti-KS antibody. RESULTS: The following changes in the coding sequence of the CHST6 gene were observed; homozygous mutation of c.1A>T (p.M1?); homozygous mutation c.599T>G (p.L200R); compound heterozygosity for c.599T>G and c.614G>A (p.R205Q); compound heterozygosity for c.494G>A (p.C165Y) and c.599T>G; heterozygous c.599T>G mutation and no other change in the coding sequence. One proband exhibited no changes. The pathogenic mutation c.599T>G (p.L200R) was in allelic association with the c.484C>G (p.R162G) polymorphism. Nine patients from seven families were of MCD type I including the subtype IA. CONCLUSION: Four different CHST6 missense mutations, of which p.C165Y is novel, were identified. Allelic association of the c.[484C>G; 599T>G] in six probands out of eight, as well as occurrence of this particular allele in a heterozygous state in one healthy control individual, supports a common founder effect for MCD in the Czech Republic.