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.
- IRRITABLE BOWEL SYNDROME
- POLYMORPHIC VARIATION
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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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