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

Maria Henström, Lena Diekmann, Ferdinando Bonfiglio, Fatemeh Hadizadeh, Eva-Maria Kuech, Maren von Köckritz-Blickwede, Louise B Thingholm, Tenghao Zheng, Ghazaleh Assadi, Claudia Dierks, Martin Heine, Ute Philipp, Ottmar Distl, Mary E Money, Meriem Belheouane, Femke-Anouska Heinsen, Joseph Rafter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Susanna Walter, Magnus Simrén, Pontus Karling, Bodil Ohlsson, Peter T Schmidt, Greger Lindberg, Aldona Dlugosz, Lars Agreus, Anna Andreasson, Emeran Mayer, John F Baines, Lars Engstrand, Piero Portincasa, Massimo Bellini, Vincenzo Stanghellini, Giovanni Barbara, Lin Chang, Michael Camilleri, Andre Franke, Hassan Y Naim, Mauro D'Amato

Journal: Gut 2018;67(2):263-270

PMID: 27872184

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Plain Language Summary

Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder which results in a lower ability to digest certain sugars, resulting in diarrhoea, abdominal pain and bloating, which are also common symptoms of Irritable Bowel Syndrome (IBS). The objective of this study was to test sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. The researchers looked at genetics in several populations with and without IBS. The researchers found that genetic mutations are associated with a 35% reduction in the activity of the SI enzymes. CSID mutations were almost twice as common in IBS patients than healthy controls. The genetic variant 15Phe was associated with diarrhoea, stool frequency and changes in the gut bacteria. The authors concluded that people with SI gene variants associated with reduced enzyme activity are more at risk of IBS. Genetic screening could help to identify individuals at increased risk of IBS, and may lead to more targeted treatment for some people with IBS.

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 () gene variants for their potential relevance in IBS.

DESIGN

We sequenced exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common 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 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

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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Address: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; 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 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.; 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.; 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.; 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.; Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.; 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.

DOI: 10.1136/gutjnl-2016-312456

Clinical Imbalances

Gastro-intestinal

Laboratory Testing

Blood Stool Tissue biopsy

Modifiable Lifestyle Factors

Diet

Nutrition Evidence Keywords

IBS IBSD Microbiome Sugars Malabsorption Genetics Bacteria Gutbacteria Carbohydratemalabsorption SNP Sucrase Isomaltase Digestiveenzymes 15Val 15Phe

Bioactive Substances

Sucrase Isomaltase

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MeSH Terms: Adult, Animals, Carbohydrate Metabolism, Inborn Errors, Case-Control Studies, Cell Line, Cell Membrane, DNA Mutational Analysis, Defecation, Diarrhea, Exons, Feces, Female, Gene Dosage, Genotype, Haplorhini, Humans, Irritable Bowel Syndrome, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sucrase-Isomaltase Complex, Transfection