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

Henström, Maria; Diekmann, Lena; Bonfiglio, Ferdinando; Hadizadeh, Fatemeh; Kuech, Eva Maria; von Köckritz-Blickwede, Maren; Thingholm, Louise B.; Zheng, Tenghao; Assadi, Ghazaleh and Dierks, Claudia, et al. (2016) In Gut
Abstract

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase- isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p. Val557Gly, p. Gly1073Asp, p. Arg1124Ter and p. Phe1745Cys) and a common SI coding polymorphism (p. Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function... (More)

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase- isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p. Val557Gly, p. Gly1073Asp, p. Arg1124Ter and p. Phe1745Cys) and a common SI coding polymorphism (p. Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p. Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. 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 coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

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@article{6913f984-7554-41d3-873c-c71bcc3edea0,
  abstract     = {<p>Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase- isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p. Val557Gly, p. Gly1073Asp, p. Arg1124Ter and p. Phe1745Cys) and a common SI coding polymorphism (p. Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p. Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. 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&lt;0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.</p>},
  author       = {Henström, Maria and Diekmann, Lena and Bonfiglio, Ferdinando and Hadizadeh, Fatemeh and Kuech, Eva Maria and von Köckritz-Blickwede, Maren and Thingholm, Louise B. and Zheng, Tenghao and Assadi, Ghazaleh and Dierks, Claudia and Heine, Martin and Philipp, Ute and Distl, Ottmar and Money, Mary E. and Belheouane, Meriem and Heinsen, Femke Anouska and Rafter, Joseph and Nardone, Gerardo and Cuomo, Rosario and Usai-Satta, Paolo and Galeazzi, Francesca and Neri, Matteo and Walter, Susanna and Simrén, Magnus and Karling, Pontus and Ohlsson, Bodil and Schmidt, Peter T. and Lindberg, Greger and Dlugosz, Aldona and Agreus, Lars and Andreasson, Anna and Mayer, Emeran and Baines, John F. and Engstrand, Lars and Portincasa, Piero and Bellini, Massimo and Stanghellini, Vincenzo and Barbara, Giovanni and Chang, Lin and Camilleri, Michael and Franke, Andre and Naim, Hassan Y. and D'Amato, Mauro},
  issn         = {0017-5749},
  language     = {eng},
  month        = {11},
  publisher    = {BMJ Publishing Group},
  series       = {Gut},
  title        = {Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome},
  url          = {http://dx.doi.org/10.1136/gutjnl-2016-312456},
  year         = {2016},
}