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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Gut. 2018 02; 67(2):263-270.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 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.

Authors+Show Affiliations

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.Internal Medicine Department, University of Maryland School of Medicine, Baltimore, Maryland, USA. Meritus Medical Center, Hagerstown, Maryland, USA.Max Planck Institute for Evolutionary Biology, Plön, Germany. Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy.Diagnosis and Therapy of Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy.S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.Gastroenterology Unit, Padova University-Hospital, Padova, Italy.Department of Medicine and Aging Sciences and CeSi, G. D'Annunzio University, Chieti, Italy.Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.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.Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.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.Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden. Stress Research Institute, Stockholm University, Stockholm, Sweden.Division of Digestive Diseases, Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, USA.Max Planck Institute for Evolutionary Biology, Plön, Germany. Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy.Gastrointestinal Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.Division of Digestive Diseases, Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, USA.Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.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.

Pub Type(s)

Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27872184

Citation

Henström, Maria, et al. "Functional Variants in the Sucrase-isomaltase Gene Associate With Increased Risk of Irritable Bowel Syndrome." Gut, vol. 67, no. 2, 2018, pp. 263-270.
Henström M, Diekmann L, Bonfiglio F, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2018;67(2):263-270.
Henström, M., Diekmann, L., Bonfiglio, F., Hadizadeh, F., Kuech, E. M., von Köckritz-Blickwede, M., Thingholm, L. B., Zheng, T., Assadi, G., Dierks, C., Heine, M., Philipp, U., Distl, O., Money, M. E., Belheouane, M., Heinsen, F. A., Rafter, J., Nardone, G., Cuomo, R., ... D'Amato, M. (2018). Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut, 67(2), 263-270. https://doi.org/10.1136/gutjnl-2016-312456
Henström M, et al. Functional Variants in the Sucrase-isomaltase Gene Associate With Increased Risk of Irritable Bowel Syndrome. Gut. 2018;67(2):263-270. PubMed PMID: 27872184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. AU - Henström,Maria, AU - Diekmann,Lena, AU - Bonfiglio,Ferdinando, AU - Hadizadeh,Fatemeh, AU - Kuech,Eva-Maria, AU - von Köckritz-Blickwede,Maren, AU - Thingholm,Louise B, AU - Zheng,Tenghao, AU - Assadi,Ghazaleh, AU - Dierks,Claudia, AU - Heine,Martin, AU - Philipp,Ute, AU - Distl,Ottmar, AU - Money,Mary E, AU - Belheouane,Meriem, AU - Heinsen,Femke-Anouska, AU - Rafter,Joseph, AU - Nardone,Gerardo, AU - Cuomo,Rosario, AU - Usai-Satta,Paolo, AU - Galeazzi,Francesca, AU - Neri,Matteo, AU - Walter,Susanna, AU - Simrén,Magnus, AU - Karling,Pontus, AU - Ohlsson,Bodil, AU - Schmidt,Peter T, AU - Lindberg,Greger, AU - Dlugosz,Aldona, AU - Agreus,Lars, AU - Andreasson,Anna, AU - Mayer,Emeran, AU - Baines,John F, AU - Engstrand,Lars, AU - Portincasa,Piero, AU - Bellini,Massimo, AU - Stanghellini,Vincenzo, AU - Barbara,Giovanni, AU - Chang,Lin, AU - Camilleri,Michael, AU - Franke,Andre, AU - Naim,Hassan Y, AU - D'Amato,Mauro, Y1 - 2016/11/21/ PY - 2016/06/16/received PY - 2016/10/29/revised PY - 2016/10/31/accepted PY - 2016/11/23/pubmed PY - 2018/3/10/medline PY - 2016/11/23/entrez KW - DIARRHOEA KW - GENETICS KW - IRRITABLE BOWEL SYNDROME KW - POLYMORPHIC VARIATION SP - 263 EP - 270 JF - Gut JO - Gut VL - 67 IS - 2 N2 - 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. SN - 1468-3288 UR - https://www.unboundmedicine.com/medline/citation/27872184/Functional_variants_in_the_sucrase_isomaltase_gene_associate_with_increased_risk_of_irritable_bowel_syndrome_ L2 - http://gut.bmj.com/cgi/pmidlookup?view=long&amp;pmid=27872184 DB - PRIME DP - Unbound Medicine ER -