https://nova.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47794 Tue 31 Jan 2023 15:19:00 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46842 Thu 01 Dec 2022 16:04:34 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20807 V1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na_V1.5. Methods: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P <.05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na_V1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na_V1.5 had the greatest effect in reducing Na_V1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na_V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.]]> Sat 24 Mar 2018 08:05:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:29828 P < .001), and diverticulosis was rare in participants younger than 40 years (0.7%). All participants with diverticulosis had sigmoid involvement. Participants with diverticulosis were more likely to report loose stools (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.20–2.96), urgency (OR, 1.64; 95% CI, 1.02–2.63), passing mucus (OR, 2.26; 95% CI, 1.08–4.72), and a high stool frequency (OR, 2.02; 95% CI, 1.11–3.65). Diverticulosis was associated with abdominal pain (OR, 2.10; 95% CI, 1.01–4.36; P = .047) and diarrhea-predominant IBS (OR, 9.55; 95% CI, 1.08–84.08; P = .04) in participants older than 60 years. The presence of anxiety and depression and self-rated health were similar in participants with and without diverticulosis. Conclusions: The prevalence of diverticulosis is age-dependent. Diverticulosis is associated with diarrhea in subjects across all age ranges. In subjects older than age 60, diverticulosis is associated with abdominal pain and diarrhea-predominant IBS/]]> Sat 24 Mar 2018 07:40:52 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:26934 KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10^-6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.]]> Sat 24 Mar 2018 07:27:31 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:53921 Mon 22 Jan 2024 16:42:54 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48303 Mon 15 May 2023 10:42:18 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42590 Fri 26 Aug 2022 09:01:19 AEST ]]>