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.

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.