المؤلفون: Bonfiglio, Ferdinando, Zheng, Tenghao, Garcia-Etxebarria, Koldo, Hadizadeh, Fatemeh, Bujanda, Luis, Bresso, Francesca, Agreus, Lars, Andreasson, Anna, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T., Karling, Pontus, Ohlsson, Bodil, Simren, 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, Camilleri, Michael, Franke, Andre, Zhernakova, Alexandra, D'Amato, Mauro

المصدر: Gastroenterology; 155(1), pp 168-179 (2018) ; ISSN: 0016-5085

مصطلحات موضوعية: Gastroenterology and Hepatology, Medical Genetics, Biobank Research, Bowel Symptoms, Genetics, SNP

الوصف: Background & Aims: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. Methods: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40–69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. Results: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10–8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10–6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10–10 in UK Biobank) and also associate with constipation-predominant IBS in women (P =.015 in the tertiary cohort) and harder stools in women (P =.0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. Conclusions: 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 ...

العلاقة: https://lup.lub.lu.se/record/81cce975-7934-4054-a019-d00312f17ba4Test; http://dx.doi.org/10.1053/j.gastro.2018.03.064Test; pmid:29626450; scopus:85049316459

الإتاحة: https://doi.org/10.1053/j.gastro.2018.03.064Test
https://lup.lub.lu.se/record/81cce975-7934-4054-a019-d00312f17ba4Test

المؤلفون: Henström, Maria, Diekmann, Lena, Bonfiglio, Ferdinando, Hadizadeh, Fatemeh, Kuech, Eva Maria, von Köckritz-Blickwede, Maren, Thingholm, Louise B., Zheng, Tenghao, Assadi, Ghazaleh, Dierks, Claudia, Heine, Martin, Philipp, Ute, Distl, Ottmar, Money, Mary E., Belheouane, Meriem, Heinsen, Femke Anouska, Rafter, Joseph, Nardone, Gerardo, Cuomo, Rosario, Usai-Satta, Paolo, Galeazzi, Francesca, Neri, Matteo, Walter, Susanna, Simrén, Magnus, Karling, Pontus, Ohlsson, Bodil, Schmidt, Peter T., Lindberg, Greger, Dlugosz, Aldona, Agreus, Lars, Andreasson, Anna, Mayer, Emeran, Baines, John F., Engstrand, Lars, Portincasa, Piero, Bellini, Massimo, Stanghellini, Vincenzo, Barbara, Giovanni, Chang, Lin, Camilleri, Michael, Franke, Andre, Naim, Hassan Y., D'Amato, Mauro

المصدر: Gut; 67(2), pp 263-270 (2018) ; ISSN: 0017-5749

مصطلحات موضوعية: Medical Genetics, Gastroenterology and Hepatology

الوصف: Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase- isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p. Val557Gly, p. Gly1073Asp, p. Arg1124Ter and p. Phe1745Cys) and a common SI coding polymorphism (p. Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p. Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

العلاقة: https://lup.lub.lu.se/record/6913f984-7554-41d3-873c-c71bcc3edea0Test; http://dx.doi.org/10.1136/gutjnl-2016-312456Test; scopus:85006058898; pmid:27872184

الإتاحة: https://doi.org/10.1136/gutjnl-2016-312456Test
https://lup.lub.lu.se/record/6913f984-7554-41d3-873c-c71bcc3edea0Test

المؤلفون: Garcia-Etxebarria, Koldo, Zheng, Tenghao, Bonfiglio, Ferdinando, Bujanda, Luis, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T., Karling, Pontus, Ohlsson, Bodil, Simren, Magnus, Walter, Susanna, Nardone, Gerardo, Cuomo, Rosario, Usai-Satta, Paolo, Galeazzi, Francesca, Neri, Matteo, Portincasa, Piero, Bellini, Massimo, Barbara, Giovanni, Jonkers, Daisy, Eswaran, Shanti, Chey, William D., Kashyap, Purna, Chang, Lin, Mayer, Emeran A., Wouters, Mira M., Boeckxstaens, Guy, Camilleri, Michael, Franke, Andre, D'Amato, Mauro

المصدر: Clinical Gastroenterology and Hepatology; 16(10), pp 1673-1676 (2018) ; ISSN: 1542-3565

مصطلحات موضوعية: Gastroenterology and Hepatology

العلاقة: https://lup.lub.lu.se/record/037dbd9a-69cb-4daa-bfdb-b07be23ee185Test; http://dx.doi.org/10.1016/j.cgh.2018.01.047Test; pmid:29408290; scopus:85046701731

الإتاحة: https://doi.org/10.1016/j.cgh.2018.01.047Test
https://lup.lub.lu.se/record/037dbd9a-69cb-4daa-bfdb-b07be23ee185Test

المؤلفون: Ancillotto, Leonardo, Rydell, Jens, Nardone, Valentina, Russo, Danilo

المصدر: Acta Chiropterologica; 16(1), pp 103-108 (2014) ; ISSN: 1508-1109

مصطلحات موضوعية: Biological Sciences, Barbastella barbastellus, bat conservation, habitat selection, island, ecology, Mediterranean

الوصف: Small islands usually show simplified ecosystems with limited availability of suitable foraging habitats for bats, thus habitat selection on islands may differ compared to the mainland. Habitats that are marginal on the mainland may be important on islands. The island of Capri consists, to a large extent, of steep limestone cliffs and Mediterranean shrubland, with virtually no forests or other habitats preferred by bats on the mainland. In this study we tested the hypothesis that in resource-limited systems, such as islands, habitats generally deemed of minor value for bat foraging, such as cliffs, may become important. We conducted an acoustic survey of bats in Capri ( SW Italy), comparing their use of Mediterranean shrubland and limestone cliffs. We found that cliffs provided the preferred foraging habitat in four of the five species tested. Noticeably, even the barbastelle bat Barbastella barbastellus, normally considered a forest specialist, selected coastal cliffs as foraging habitat. Our observations indicate that the paucity of foraging habitats on islands may strongly alter the habitat use by bats. This has important implications for conservation of bats in insular environments.

العلاقة: https://lup.lub.lu.se/record/4655968Test; http://dx.doi.org/10.3161/150811014X683318Test; wos:000340855000010; scopus:84906245022

الإتاحة: https://doi.org/10.3161/150811014X683318Test
https://lup.lub.lu.se/record/4655968Test

المؤلفون: Beyder, Arthur, Mazzone, Amelia, Strege, Peter R., Tester, David J., Saito, Yuri A., Bernard, Cheryl E., Enders, Felicity T., Ek, Weronica E., Schmidt, Peter T., Dlugosz, Aldona, Lindberg, Greger, Karling, Pontus, Ohlsson, Bodil, Gazouli, Maria, Nardone, Gerardo, Cuomo, Rosario, Usai-Satta, Paolo, Galeazzi, Francesca, Neri, Matteo, Portincasa, Piero, Bellini, Massimo, Barbara, Giovanni, Camilleri, Michael, Locke III, G. Richard, Talley, Nicholas J., D'Amato, Mauro, Ackerman, Michael J., Farrugia, Gianrico

المصدر: Gastroenterology; 146(7), pp 1659-1668 (2014) ; ISSN: 1528-0012

مصطلحات موضوعية: Gastroenterology and Hepatology, Genetics, GI Motility, Voltage-Gated Sodium Channel, Polymorphism

الوصف: BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. 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(V)1.5. 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(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 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(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

العلاقة: https://lup.lub.lu.se/record/4552456Test; http://dx.doi.org/10.1053/j.gastro.2014.02.054Test; wos:000336500900021; scopus:84901230979; pmid:24613995

الإتاحة: https://doi.org/10.1053/j.gastro.2014.02.054Test
https://lup.lub.lu.se/record/4552456Test