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Functional Variants in the Sucrase–Isomaltase Gene Associate With Gut Online First, published on November 21, 2016 as 10.1136/gutjnl-2016-312456 Neurogastroenterology ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2016-312456 on 21 November 2016. Downloaded from Functional variants in the sucrase–isomaltase gene associate with increased risk of irritable bowel syndrome Maria Henström,1 Lena Diekmann,2 Ferdinando Bonfiglio,1 Fatemeh Hadizadeh,1 Eva-Maria Kuech,2 Maren von Köckritz-Blickwede,2 Louise B Thingholm,3 Tenghao Zheng,1 Ghazaleh Assadi,1 Claudia Dierks,4 Martin Heine,2 Ute Philipp,4 Ottmar Distl,4 Mary E Money,5,6 Meriem Belheouane,7,8 Femke-Anouska Heinsen,3 Joseph Rafter,1 Gerardo Nardone,9 Rosario Cuomo,10 Paolo Usai-Satta,11 Francesca Galeazzi,12 Matteo Neri,13 Susanna Walter,14 Magnus Simrén,15,16 Pontus Karling,17 Bodil Ohlsson,18,19 Peter T Schmidt,20 Greger Lindberg,20 Aldona Dlugosz,20 Lars Agreus,21 Anna Andreasson,21,22 Emeran Mayer,23 John F Baines,7,8 Lars Engstrand,24 Piero Portincasa,25 Massimo Bellini,26 Vincenzo Stanghellini,27 Giovanni Barbara,27 Lin Chang,23 Michael Camilleri,28 Andre Franke,3 Hassan Y Naim,2 Mauro D’Amato1,29,30 ▸ Additional material is ABSTRACT published online only. To view Objective IBS is a common gut disorder of uncertain Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ pathogenesis. Among other factors, genetics and certain gutjnl-2016-312456). foods are proposed to contribute. Congenital sucrase– isomaltase deficiency (CSID) is a rare genetic form of What is already known on this subject? disaccharide malabsorption characterised by diarrhoea, ▸ fi fi IBS shows genetic predisposition, but speci c For numbered af liations see abdominal pain and bloating, which are features end of article. causative genes have not been unequivocally common to IBS. We tested sucrase–isomaltase (SI) gene identified. Correspondence to variants for their potential relevance in IBS. ▸ Certain foods, particularly carbohydrates, are Dr Mauro D’Amato, Unit of Design We sequenced SI exons in seven familial cases, among the proposed triggers of IBS symptoms, http://gut.bmj.com/ Clinical Epidemiology, and screened four CSID mutations (p.Val557Gly, p. at least in some patients. Department of Medicine Solna, ▸ – SI Karolinska Institutet, Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a The sucrase isomaltase ( ) gene, which is Eugeniahemmet T2, Karolinska common SI coding polymorphism (p.Val15Phe) in a mutated in hereditary recessive forms of University Hospital, Solna multicentre cohort of 1887 cases and controls. We sucrose intolerance (congenital sucrase– 17176, Stockholm, Sweden; studied the effect of the 15Val to 15Phe substitution on isomaltase deficiency (CSID)) characterised by [email protected] SI function in vitro. We analysed p.Val15Phe genotype in diarrhoea, represents an excellent candidate to MH and LD, shared first relation to IBS status, stool frequency and faecal play a role in IBS predisposition. on September 30, 2021 by guest. Protected copyright. authors; FB, FHa, E-MK, microbiota composition in 250 individuals from the shared second authors; HYN general population. fi and MD’A shared last authors. What are the new ndings? Results CSID mutations were more common in patients ▸ Although rare, CSID mutations with known Received 16 June 2016 than asymptomatic controls (p=0.074; OR=1.84) and defective disaccharidase (SI) properties are Revised 29 October 2016 Exome Aggregation Consortium reference sequenced found more often in patients with IBS than Accepted 31 October 2016 individuals (p=0.020; OR=1.57). 15Phe was detected in controls. 6/7 sequenced familial cases, and increased IBS risk in ▸ A common SI variant (15Phe), which shows – case control and population-based cohorts, with best reduced enzymatic activity in vitro, is strongly evidence for diarrhoea phenotypes (combined associated with increased risk of IBS. p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency How might it impact on clinical practice in (p=0.026) and Parabacteroides faecal microbiota the foreseeable future? abundance (p=0.0024). The SI protein with 15Phe ▸ Screening for functional SI genetic variants may exhibited 35% reduced enzymatic activity in vitro help the identification of subsets of patients compared with 15Val (p<0.05). with suboptimal carbohydrate (disaccharide) Conclusions SI gene variants coding for To cite: Henström M, digestion rates. disaccharidases with defective or reduced enzymatic Diekmann L, Bonfiglio F, ▸ This holds potential for stratifying patients with activity predispose to IBS. This may help the et al. Gut Published Online IBS and personalising treatment options in First: [please include Day identification of individuals at risk, and contribute to those with SI genetic defects. Month Year] doi:10.1136/ personalising treatment options in a subset of patients. gutjnl-2016-312456 Henström M, et al. Gut 2016;0:1–8. doi:10.1136/gutjnl-2016-312456 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Neurogastroenterology INTRODUCTION (1) sequencing of the entire SI coding region in seven familial IBS is the most common gut disorder, affecting more than 10% cases of severe postprandial IBS-D; (2) detailed in vitro func- Gut: first published as 10.1136/gutjnl-2016-312456 on 21 November 2016. Downloaded from of the general population in Westernised countries; it is asso- tional characterisation of a common coding variant leading to ciated with significant healthcare expenditure and considerably the amino acid change p.Val15Phe in the SI protein; (3) geno- affects patients’ quality of life.12IBS is a functional GI disorder typing and association testing of the most common known (FGID), diagnosed and classified according to expert consensus CSID mutations,19 and the p.Val15Phe variant in 1887 indivi- guidelines, the Rome criteria, based on recurrent symptoms duals from four independent cohorts of IBS cases and controls; including abdominal discomfort or pain associated with diar- (4) in a small Swedish general population sample, pilot analyses rhoea (IBS-D), constipation (IBS-C) or mixed symptoms of correlation between p.Val15Phe genotype and (i) IBS status (IBS-M).3 The aetiology of IBS is unknown, although psycho- (ii) stool frequency and (iii) faecal microbiota composition. The logical stressors, prior infections, dietary irritants, gut dysbiosis, results obtained from these experiments support a role for SI epithelial barrier dysfunction and mucosal immune activation genetic variation in IBS. are among the recognised risk factors.4 Genetic predisposition has been demonstrated in classical family/twin studies and epi- MATERIALS AND METHODS demiological surveys, but unequivocal susceptibility genes have Study subjects fi 5 yet to be identi ed. Because of incomplete understanding of IBS probands the mechanisms underpinning IBS pathophysiology, effective Eight Caucasian individuals, namely seven postprandial IBS-D treatment options are limited and primarily aimed at targeting cases (Rome criteria) and one asymptomatic relative, from four fi symptoms, resulting in suboptimal ef cacy. unrelated families were selected for sequencing of the SI gene The role of nutrition and dietary factors is increasingly recog- (see online supplementary figure S1). Two of the symptomatic nised in IBS. Patients (particularly IBS-D) often report postpran- patients were parents of two of the probands. Patients experi- 6 dial symptoms, and many IBS sufferers claim that certain foods enced meal-related symptoms for more than 2 years and were 7 are the triggering factors. Avoidance of carbohydrates due to currently using digestive enzyme supplements to reduce post- perceived maldigestion is common, and a diet low in ferment- prandial symptoms (described more in detail in the online able oligosaccharides, disaccharides, monosaccharides and supplementary methods). polyols (FODMAPs, which are poorly absorbed in the small intestine) has been proposed as effective in reducing IBS symp- IBS case–control cohorts toms.89At least in some patients, the food–symptom relation We studied a total of 1031 IBS cases and 856 controls, all may involve malabsorption of carbohydrates due to inefficient non-Hispanic/Latino whites from four independent cohorts enzymatic breakdown of polysaccharides, which may find indir- from Sweden, Italy and USA, who have been described in detail ect support in the observed symptom improvement in patients – elsewhere and already included in previous genetic studies.20 25 with postprandial IBS-D treated with pancrealipase,10 and the Their demographics and clinical characteristics are reported in detection of disaccharidase deficiency in children with FGID.11 table 1, and detailed information is provided in the online Sucrase–isomaltase (SI) deficiency (also called sucrose intoler- supplementary methods and table S1. ance) is a form of carbohydrate malabsorption characterised by http://gut.bmj.com/ diarrhoea, abdominal pain and bloating, which are features common to IBS-D. The symptoms result from defective glucosi- PopCol participants dase (disaccharidase) activity of the SI enzyme in the small intes- The Population-based Colonoscopy study (PopCol) is a cohort tine.12 This enzyme is key to the degradation of starch and representative of the general population from Stockholm, sugars digested daily,13 and its functional impairment leads to Sweden, which includes a data-rich set of individuals with avail- colonic accumulation of unabsorbed
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