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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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