title: Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
abstract: 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.
  
  
  
  We sequencedSIexons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a commonSIcoding 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.
  
  
  
  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) andParabacteroidesfaecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05).
  
  
  
  SIgene 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.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Henström
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Diekmann
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Bonfiglio
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Hadizadeh
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Kuech
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Louise B
authors.initials: LB
authors.lastname: Thingholm
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tenghao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Assadi
authors.affiliation: Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dierks
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heine
authors.affiliation: Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Philipp
authors.affiliation: Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Ottmar
authors.initials: O
authors.lastname: Distl
authors.affiliation: Internal Medicine Department, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Meritus Medical Center, Hagerstown, Maryland, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Money
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany.|Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Meriem
authors.initials: M
authors.lastname: Belheouane
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Femke-Anouska
authors.initials: FA
authors.lastname: Heinsen
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rafter
authors.affiliation: Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Nardone
authors.affiliation: Diagnosis and Therapy of Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Cuomo
authors.affiliation: S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Usai-Satta
authors.affiliation: Gastroenterology Unit, Padova University-Hospital, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Galeazzi
authors.affiliation: Department of Medicine and Aging Sciences and CeSi, G. D'Annunzio University, Chieti, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Neri
authors.affiliation: Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Walter
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Magnus
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authors.lastname: Simrén
authors.affiliation: Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Karling
authors.affiliation: Division of Internal Medicine, Department of Clinical Sciences, Skåne University Hospital, Malmö, Sweden.|Division of Internal Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.affiliation: Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Schmidt
authors.affiliation: Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Greger
authors.initials: G
authors.lastname: Lindberg
authors.affiliation: Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Aldona
authors.initials: A
authors.lastname: Dlugosz
authors.affiliation: Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.
authors.forename: Lars
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authors.lastname: Agreus
authors.affiliation: Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.|Stress Research Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Andreasson
authors.affiliation: Division of Digestive Diseases, Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors.forename: Emeran
authors.initials: E
authors.lastname: Mayer
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany.|Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: John F
authors.initials: JF
authors.lastname: Baines
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Engstrand
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Portincasa
authors.affiliation: Gastrointestinal Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bellini
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Stanghellini
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barbara
authors.affiliation: Division of Digestive Diseases, Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Science Foundation, Bilbao, Spain.|Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mauro
authors.identifier: 0000-0003-2743-5197
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D000328:Adult; D000818:Animals; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D004252:DNA Mutational Analysis; D003672:Defecation / Q000235:genetics; D003967:Diarrhea / Q000209:etiology; D005091:Exons; D005243:Feces / Q000382:microbiology; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D000882:Haplorhini; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013394:Sucrase-Isomaltase Complex / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D013394:Sucrase-Isomaltase Complex
keywords: DIARRHOEA; GENETICS; IRRITABLE BOWEL SYNDROME; POLYMORPHIC VARIATION