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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
Karolinska Institute, Sweden.
University of Vet Medical Hannover, Germany.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
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2018 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 67, no 2, p. 263-270Article in journal (Refereed) Published
Abstract [en]

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase 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 (pamp;lt;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.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP , 2018. Vol. 67, no 2, p. 263-270
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Medical Genetics
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URN: urn:nbn:se:liu:diva-144435DOI: 10.1136/gutjnl-2016-312456ISI: 000419604800011PubMedID: 27872184OAI: oai:DiVA.org:liu-144435DiVA, id: diva2:1176709
Note

Funding Agencies|Swedish Research Council (Vetenskapsradet); Olle Engkvist Byggmastare Foundation; Medical Need Europe AB; European Union Seventh Framework Programme (ESGI); German Research Foundation (DFG) [1743, 306]; German Research Foundation DFG; Soderbergs Foundation; NIH [P50 DK64539, P01 DK33506, DK047343]

Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-01-23

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Walter, Susanna
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of GastroentorologyCenter for Medical Image Science and Visualization (CMIV)
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