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Functional variants in the sucrase–isomaltase gene associate with increased risk of irritable bowel syndrome
  1. Maria Henström1,
  2. Lena Diekmann2,
  3. Ferdinando Bonfiglio1,
  4. Fatemeh Hadizadeh1,
  5. Eva-Maria Kuech2,
  6. Maren von Köckritz-Blickwede2,
  7. Louise B Thingholm3,
  8. Tenghao Zheng1,
  9. Ghazaleh Assadi1,
  10. Claudia Dierks4,
  11. Martin Heine2,
  12. Ute Philipp4,
  13. Ottmar Distl4,
  14. Mary E Money5,6,
  15. Meriem Belheouane7,8,
  16. Femke-Anouska Heinsen3,
  17. Joseph Rafter1,
  18. Gerardo Nardone9,
  19. Rosario Cuomo10,
  20. Paolo Usai-Satta11,
  21. Francesca Galeazzi12,
  22. Matteo Neri13,
  23. Susanna Walter14,
  24. Magnus Simrén15,16,
  25. Pontus Karling17,
  26. Bodil Ohlsson18,19,
  27. Peter T Schmidt20,
  28. Greger Lindberg20,
  29. Aldona Dlugosz20,
  30. Lars Agreus21,
  31. Anna Andreasson21,22,
  32. Emeran Mayer23,
  33. John F Baines7,8,
  34. Lars Engstrand24,
  35. Piero Portincasa25,
  36. Massimo Bellini26,
  37. Vincenzo Stanghellini27,
  38. Giovanni Barbara27,
  39. Lin Chang23,
  40. Michael Camilleri28,
  41. Andre Franke3,
  42. Hassan Y Naim2,
  43. Mauro D'Amato1,29,30
  1. 1 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  2. 2 Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany
  3. 3 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  4. 4 Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany
  5. 5 Internal Medicine Department, University of Maryland School of Medicine, Baltimore, Maryland, USA
  6. 6 Meritus Medical Center, Hagerstown, Maryland, USA
  7. 7 Max Planck Institute for Evolutionary Biology, Plön, Germany
  8. 8 Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany
  9. 9 Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
  10. 10 Diagnosis and Therapy of Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
  11. 11 S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy
  12. 12 Gastroenterology Unit, Padova University-Hospital, Padova, Italy
  13. 13 Department of Medicine and Aging Sciences and CeSi, G. D'Annunzio University, Chieti, Italy
  14. 14 Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  15. 15 Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  16. 16 Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA
  17. 17 Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  18. 18 Division of Internal Medicine, Department of Clinical Sciences, Skåne University Hospital, Malmö, Sweden
  19. 19 Division of Internal Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
  20. 20 Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
  21. 21 Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden
  22. 22 Stress Research Institute, Stockholm University, Stockholm, Sweden
  23. 23 Division of Digestive Diseases, Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, USA
  24. 24 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
  25. 25 Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, Bari, Italy
  26. 26 Gastrointestinal Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
  27. 27 Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
  28. 28 Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA
  29. 29 BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Science Foundation, Bilbao, Spain
  30. 30 Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Dr Mauro D'Amato, Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Eugeniahemmet T2, Karolinska University Hospital, Solna 17176, Stockholm, Sweden; mauro.damato{at}


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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  • MH and LD, shared first authors; FB, FHa, E-MK, shared second authors; HYN and MD'A shared last authors.

  • Contributors HYN and MDA: study concept, design and supervision; MvK-B, CD, MHei, UP, OD, MEM, GN, RC, PU-S, FG, MN, SW, MS, PK, BO, PTS, GL, AD, LA, AA, EM, LE, PP, MB, VS, GB, LC and MC: characterisation of study individuals and data acquisition; LD, E-MK and HYN: functional in vitro experiments; FHa, LBT, MB, F-AH, JFB, AF and MDA: microbiota analyses; GA and MDA: genotyping; MHe, LD, FH, FB, TZ, MB, F-AH, JR, JFB, AF, HYN and MDA: data integration, analysis and interpretation; MHe, LD, HYN and MDA: drafting of the manuscript with input and critical revision from all other authors.

  • Funding This work was supported by grants from the Swedish Research Council (Vetenskapsrådet), the Olle Engkvist Byggmästare Foundation and an unrestricted research grant from Medical Need Europe AB to MDA; the European Union Seventh Framework Programme (FP7/2007–2013, ESGI) to MDA and AF; the German Research Foundation (DFG) Research Training Grant 1743 and Excellence Cluster 306 to AF; the German Research Foundation DFG to HYN; the Soderbergs Foundation to LE; NIH grants P50 DK64539, P01 DK33506 and DK047343 to EM and LC.

  • Competing interests The work was partially financed by an unrestricted grant from Medical Need Europe AB to MDA. MDA and HYN have received unrestricted research grants and lecturing honoraria from QOL Medical, and LC has served on a scientific advisory board for QOL Medical.

  • Ethics approval Local ethics committees at Karolinska Institutet, Mayo Clinic, University of California, Los Angeles (UCLA), Bologna University, University of Veterinary Medicine Hannover.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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