Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients
Koldo Garcia-Etxebarria, Tenghao Zheng, Ferdinando Bonfiglio, Luis Bujanda, Aldona Dlugosz, Greger Lindberg, Peter T Schmidt, Pontus Karling, Bodil Ohlsson, Magnus Simren, Susanna Walter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Piero Portincasa, Massimo Bellini, Giovanni Barbara, Daisy Jonkers, Shanti Eswaran, William D Chey, Purna Kashyap, Lin Chang, Emeran A Mayer, Mira M Wouters, Guy Boeckxstaens, Michael Camilleri, Andre Franke, Mauro D'Amato, Koldo Garcia-Etxebarria, Tenghao Zheng, Ferdinando Bonfiglio, Luis Bujanda, Aldona Dlugosz, Greger Lindberg, Peter T Schmidt, Pontus Karling, Bodil Ohlsson, Magnus Simren, Susanna Walter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Piero Portincasa, Massimo Bellini, Giovanni Barbara, Daisy Jonkers, Shanti Eswaran, William D Chey, Purna Kashyap, Lin Chang, Emeran A Mayer, Mira M Wouters, Guy Boeckxstaens, Michael Camilleri, Andre Franke, Mauro D'Amato
Abstract
Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).
Conflict of interest statement
Conflicts of interest
The project has been partially supported by an unrestricted research grant from QOL Medical to MDA.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
References
- Diaz-Sotomayor M, Quezada-Calvillo R, Avery SE, et al. Maltase-glucoamylase modulates gluconeogenesis and sucrase-isomaltase dominates starch digestion glucogenesis. J Pediatr Gastroenterol Nutr. 2013;57:704–712.
- Naim HY, Heine M, Zimmer K-P. Congenital sucrase-isomaltase deficiency: heterogeneity of inheritance, trafficking, and function of an intestinal enzyme complex. J Pediatr Gastroenterol Nutr. 2012;55:S13–S20.
- Henström M, Diekmann L, Bonfiglio F, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2016;0:1–8. doi: 10.1136/gutjnl-2016-312456.
- Uhrich S, Wu Z, Huang J-Y, et al. Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID. J Pediatr Gastroenterol Nutr. 2012;55:S34–S35.
- Ek WE, Reznichenko A, Ripke S, et al. Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts. Gut. 2015;64:1774–1782.
- Beyder A, Mazzone A, Strege PR, et al. Loss-of-function of the voltage-gated sodium channel NaV1. 5 (Channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014;146:1659–1668.
- Wouters MM, Lambrechts D, Knapp M, et al. Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome. Gut. 2014;63:1103–1111.
- Mujagic Z, Tigchelaar EF, Zhernakova A, et al. A novel biomarker panel for irritable bowel syndrome and the application in the general population. Sci Rep. 2016;6:26420.
Source: PubMed