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Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.

  • Author(s): 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
  • et al.
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).

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