Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

Bonfiglio, Ferdinando; Zheng, Tenghao; García-Etxebarria, Koldo; Hadizadeh, Fatemeh; Bujanda, Luís; Bresso, Francesca; Agréus, Lars; Andréasson, Anna; Dlugosz, Aldona; Lindberg, Greger; Schmidt, Peter T.; Karling, Pontus; Ohlsson, Bodil; Simrén, Magnus; Walter, Susanna; Nardone, Gerardo; Cuomo, Rosario; Usai-Satta, Paolo; Galeazzi, Francesca; Neri, Matteo; Portincasa, Piero; Bellini, Massimo; Barbara, Giovanni; Latiano, Anna; Hübenthal, Matthias; Thijs, Vincent; Netea, Mihai G.; Jonkers, Daisy; Chang, Lin; Mayer, Emeran A.; Wouters, Mira M.; Boeckxstaens, Guy E.; Camilleri, Michael; Franke, André; Zhernakova, Alexandra; D’Amato, Mauro

doi:10.1053/j.gastro.2018.03.064

Cited by 59 publications

(69 citation statements)

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“…In order to explore this hypothesis, we tested the rs7940681 SNP for association with IBS in a meta‐analysis of association data extracted from 2 large genome‐wide association studies recently published by Bonfiglio et al . (47, 48): as shown in Table 4 , the A allele allowing Gli binding and repression at the ANO1 promoter was also weakly but significantly associated with small effects on IBS risk in this analysis.…”

Section: Resultssupporting

confidence: 54%

Direct repression of anoctamin 1 ( ANO1 ) gene transcription by Gli proteins

et al. 2019

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The Ca2+‐activated Cl− channel, anoctamin 1 (Ano1, also known as transmembrane protein 16A) contributes to intestinal pacemaking, fluid secretion, cellular excitability, and tissue development. The human ANO1 promoter contains binding sites for the glioma‐associated oncogene (Gli) proteins. We investigated regulation of ANO1 transcription by Gli. ANO1 promoter activity was determined using a luciferase reporter system. Binding and functional effects of Glis on ANO1 transcription and expression were demonstrated by chromatin immunoprecipitation, small interfering RNA knockdown, PCR, immunolabeling, and recordings of Ca2+‐activated Cl− currents in human embryonic kidney 293 (HEK293) cells. Results from previous genome‐wide association studies were used to test ANO1 promoter polymorphisms for association with disease. Gli1 and Gli2 bound to the promoter and repressed ANO1 transcription. Repression depended on Gli binding to a site close to the ANO1 transcriptional start site. Mutation of this site prevented Gli binding and transcriptional repression. Knockdown of Gli expression and inhibition of Gli activity increased expression of ANO1 RNA and Ca2+‐activated Cl− currents in HEK293 cells. A single‐nucleotide polymorphism prevented Gli binding and showed association with irritable bowel syndrome. We conclude that Gli1 and Gli2 repress ANO1 by a novel mechanism that is independent of Gli cleavage and that has a role in gastrointestinal function.—Mazzone, A., Gibbons, S. J., Eisenman, S. T., Strege, P. R., Zheng, T., D'Amato, M., Ordog, T., Fernandez‐Zapico, M. E., Farrugia, G. Direct repression of anoctamin 1 (ANO1) gene transcription by Gli proteins. FASEB J. 33, 6632–6642 (2019). http://www.fasebj.org

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Section: Resultssupporting

confidence: 54%

Direct repression of anoctamin 1 ( ANO1 ) gene transcription by Gli proteins

et al. 2019

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“…Blocking dopamine D2 receptors encoded by this gene in the chemoreceptor trigger zone relieves 23 nausea and in the gastrointestinal tract increases motility 61 . A previous study reported that rs10512344 is the 24 only one SNP genome-wide significantly associated (P = 3.6E-8) with IBS using UKB data 20 . Both the IBS (lead 25 SNP: rs112243849, P = 7.5E-8) and IBS + M (lead SNP: rs7861675, P = 1.2E-7) phenotypes in our study 26 reconfirmed the association between this locus and IBS at the genome-wide suggestive level.…”

Section: Introductionmentioning

confidence: 96%

“…These loci implicate pathways such as 28 autophagy and the IL-17/IL-23 axis and provide insights into IBD pathogenesis 15 . While IBD has been 1 extensively studied through the GWAS paradigm, only a few GWASs for GORD 16 , PUD 17 and IBS [18][19][20] have been 2 conducted to date, most of which were under-powered. 3Here, we aim to identify genetic susceptibility factors for GORD, PUD, IBS using the genome-wide 4 association study (GWAS) paradigm.…”

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confidence: 99%

Genome-wide association study of gastrointestinal disorders reinforces the link between the digestive tract and the nervous system

Murray

Byrne

et al. 2019

Preprint

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11Genetic factors are recognized to contribute to common gastrointestinal (GI) diseases such as gastro-12 oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS) and 13 inflammatory bowel disease (IBD). We conducted genome-wide association analyses based on 456,414 14 individuals and identified 27 independent and significant loci for GORD, PUD and IBS, including SNPs 15 associated with PUD at or near genes MUC1, FUT2, PSCA and CCKBR, for which there are previously 16 established roles in Helicobacter pylori infection, response to counteract infection-related damage, gastric acid 17 secretion and gastrointestinal motility. Post-GWAS analyses implicate putative functional links between the 18 nervous system and gastrointestinal tract for GORD, PUD and IBS, including the central nervous system, the 19 enteric nervous system and their connection. Mendelian Randomisation analyses imply potentially bi-20 directional causality (the risk of GORD in liability to major depression and the risk of major depression in 21 liability to GORD) or pleiotropic effect between them. A stronger genetic similarity among GORD, PUD and IBS 22 than between these disorders and IBD is reported. These findings advance understanding the role of genetic 23 variants in the etiology of GORD, PUD and IBS and add biological insights into the link between the nervous 24 system and the gastrointestinal tract. 25 1Gastrointestinal (GI) diseases are highly prevalent in western countries. They use substantial health care 2 resources, are a heavy societal economic burden 1,2 , and impact the quality of life of those affected. Common 3 GI disorders include gastro-oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel 4 syndrome (IBS) and inflammatory bowel disease (IBD). In GORD, the stomach contents leak back from the 5 stomach into the esophagus 3 . PUD involves breaks (ulcers) in the inner lining of the digestive tract, usually 6 located in the stomach or proximal duodenum. IBS is a chronic functional disorder of the GI system. Patients 7 with IBS often manifest abdominal pain and altered bowel habit, with either predominantly diarrhea, 8 constipation or both. IBD includes Crohn's disease (CD) and ulcerative colitis (UC), which are chronic idiopathic 9 disorders causing inflammation of the GI tract. 10 GORD is a multifactorial disorder and is more common in individuals with obesity and hiatal hernia 4 . 11Lifetime risk estimates of GORD have a wide range (9%-26%), with a sample size-weighted mean of 15% 5 . An 12 increase in the prevalence of GORD since 1995 has been reported 5 . PUD is a complex disorder, for which 13Helicobacter pylori infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are the main risk 14 factors 6 . The development of infection-relevant PUD is recognised to be a multistep process, with 15 contributions from both Helicobacter pylori infection and subsequent inflammation and damage of mucosa 6 . 16Eradicating Helicobacter pylori is effective for i...

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“…Impaired baroreflex pathways have been found in familial dysautonomia [31], which is not supported in our cohort with a very low prevalence of orthostatic hypotension. The found association between gene mutations of IKBKAP and self-reported IBS may reflect that many patients with GI symptoms are not properly examined [15], and could have other diagnoses of autonomic dysautonomia with secondary GI symptoms [9][10][11].…”

Section: Discussionmentioning

confidence: 99%

“…The autonomic dysfunction previously described in IBS may rather be a secondary response to peripheral and/or central hypersensitization [4,13,14], than of primary, etiological importance. On the other hand, genetic studies have shown associations between IBS and gene variants of locus 9q31.2, including IKBKAP [15], gene variants found in patients with familial dysautonomia, who also express a high prevalence of GI symptoms [16].…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to diarrhea is related to hemodynamic markers of sympathetic activation in the general population

Hamrefors

Fedorowski

Ohlsson

2019

Scandinavian Journal of Gastroenterology

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Objectives: Functional gastrointestinal (GI) symptoms, such as IBS (irritable bowel syndrome), have been suggested to be associated with autonomic neuropathy. We therefore examined associations between hemodynamic indices of autonomic control, functional GI symptoms and stress in a population-based cohort. Methods and materials: The study included 2094 participants of the Malm€ o Offspring Study (mean age 40.6 ± 13.8 years, 53.9% women). 509 (24.3%) reported having GI symptoms the last 2 weeks, without having organic GI disease, and 347 subjects (16.6%) reported IBS. Office and ambulatory 24-h systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were measured. Associations between hemodynamic parameters and abdominal pain, diarrhea, constipation, bloating and flatulence, vomiting and nausea and psychological well-being according to the visual analog scale for IBS (VAS-IBS), and stress, were performed by Spearman's correlation test and linear regression models. Results: Subjects who reported GI symptoms had lower office supine and standing DBP and lower 24 h SBP and DBP compared with those without GI symptoms. Regarding specific symptoms, diarrhea was correlated with 24-h measurements of SBP (rs ¼ 0.197), DBP (rs ¼ 0.173) and heart rate (rs ¼ 0.134). Subjects with the most severe diarrhea had higher 24-h SBP (125.2 vs. 119.0 mmHg; p ¼ .038), DBP (74.0 vs. 69.0 mmHg; p ¼ .033) and heart rate (74.5 vs 71.1 beats/minute; p ¼ .048), after adjustments for confounders, compared to the other. There were no associations between other GI symptoms, IBS, stress and hemodynamic alterations. Conclusion: Functional diarrhea was associated with hemodynamic indices of sympathetic activation, supporting a possible role of the autonomic nervous system in diarrhea. ARTICLE HISTORY

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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

Abstract: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

Cited by 59 publications

References 52 publications

Direct repression of anoctamin 1 ( ANO1 ) gene transcription by Gli proteins

Direct repression of anoctamin 1 ( ANO1 ) gene transcription by Gli proteins

Genome-wide association study of gastrointestinal disorders reinforces the link between the digestive tract and the nervous system

Susceptibility to diarrhea is related to hemodynamic markers of sympathetic activation in the general population

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