Functional variants in the sucrase isomaltase gene associate with increased risk of irritable bowel syndrome

Gut. 2018 Feb;67(2):263-270. doi: 10.1136/gutjnl-2016-312456. Epub 2016 Nov 21.

PMID: 27872184

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

Summary: In this study, sucrase–isomaltase (SI) gene variants were investigated for their potential role in IBS. It has been found that SI gene variants encoding disaccharidases with reduced enzymatic activity predispose to IBS.

Abstract

Objective: Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, all of which are symptoms of irritable bowel syndrome (IBS). In this study, sucrase–isomaltase (SI) gene variants were investigated for their potential role in IBS.

Design: In a multicenter cohort of 1887 cases and controls, SI exons in seven familial cases were sequenced and four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter, and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) were screened. The effect of the 15Val to 15Phe substitution on SI function was investigated in vitro. In 250 people from the general population, p.Val15Phe genotype was analysed in relation to IBS, stool frequency, and faecal microbiota composition.

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 that code for disaccharidases with reduced enzymatic activity predispose to IBS. This may aid in the identification of at-risk individuals and contribute to the personalization of treatment options in a subset of patients. Keywords: congenital sucrase-isomaltase deficiency, irritable bowel syndrome, functional variant