Increased Prevalence of Rare Sucrase-isomaltase (SI) Pathogenic Variants in Irritable Bowel Syndrome Patients

Clin Gastroenterol Hepatol. 2018 Oct;16(10):1673-1676. doi: 10.1016/j.cgh.2018.01.047. Epub 2018 Feb 21.

PMID: 29408290

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

Summary: This study aims to determine if (dys-)functional SI variants which causes CSID, are associated with IBS risk. The results provide further evidence about the association of rare functionally deleterious SI variations and IBS susceptibility. Further study is needed on the SI rare pathogenic variant (SI-RPV) prevalence in IBS patients.

Abstract

Background: Irritable bowel syndrome (IBS) patients often associate their symptoms to specific foods. Congenital sucrase-isomaltase deficiency (CSID) that is caused by recessive mutations in the SI gene (coding for the disaccharidase that digests sucrose and 60% of dietary starch), leads to clinical features of IBS by an accumulation of undigested carbohydrates in the colon, resulting in bowel symptoms. As a result, in a previous study it is hypothesized that CSID variants that reduce SI enzymatic activity may contribute to the development of IBS symptoms. An association was found between an increased risk of IBS and 4 rare loss-of-function variants usually found in (homozygous) CSID patients, since carriers (heterozygous) of these rare variants were more prevalent in patients than in controls.

Aim and Methods: The current study used a two-step computational and experimental strategy to determine if other (dys-)functional SI variants, in addition to known CSID mutations, are associated with IBS risk. First the aim was to identify all SI rare pathogenic variants (SI-RPVs) using integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; then, genotype data were examined from 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).

Conclusion: This study provides further evidence about the association of rare functionally deleterious SI variations and IBS susceptibility. The findings of higher SI-RPV prevalence in IBS requires further studies. This may have the potential to identify groups among IBS patients for individualized treatment.