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      Increased Prevalence of Rare Sucrase-isomaltase ( SI) Pathogenic Variants in Irritable Bowel Syndrome Patients

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      Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

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          Abstract

          Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch) 1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms. 2 Hence, in a previous study, 3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls. 1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC). Methods Study Subjects A total of 2207 IBS patients (598 IBS with constipation [IBS-C], 952 IBS with diarrhea [IBS-D], 503 IBS with alternating constipation and diarrhea, and 154 unsubtyped IBS according to Rome Criteria) of European ancestry were included on the basis of available genotype data from the bellygenes initiative study (www.bellygenes.org). On approval from local ethical committees, IBS patients were recruited at tertiary centers in Sweden, The Netherlands, Belgium, Italy, and United States as described in detail in previous publications, including former genetic studies of IBS. 5–8 Ethnically matched (non-Finnish, European ancestry; N = 33,370) reference population frequency of relevant SI-RVPs were extracted from ExAC (http://exac.broadinstitute.org). Selection of Sucrase-isomaltase Rare Pathogenic Variants An inventory of all SI rare variants (minor allele frequency <1%) was created by extracting single nucleotide polymorphism data from dbSNP (http://www.ncbi.nlm.nih.gov/snp/). Sequential data processing with M-CAP (http://bejerano.stanford.edu/MCAP) and CADD (http://cadd.gs.washington.edu/) was then performed to identify and select SI-RPVs. These computational resources were used because of their documented power to predict deleteriousness (pathogenicity) of DNA substitutions for clinical utility, assigning priority to M-CAP scores (pathogenicity cutoff >0.025, 5% misclassification rate) over CADD scores (pathogenicity cutoff >0.20, 26% misclassification rate). Genotype Quality Control and Statistical Analysis Before extraction of SI-RPV data, stringent quality control filters were applied to available IBS patients’ Illumina HumanCoreExome genotype data, including per-sample and per-marker success rate, relatedness, and removal of population outliers based on principal component analysis. To avoid uncertainty, only observed (not imputed) SI-RPV genotypes were used, and allele calls were verified by visual inspection of individual cluster plots by using Evoker (www.sanger.ac.uk/science/tools/evoker). Population reference genotypes were only included for SI-RVPs with data available from >95% ExAC individuals. Association testing was performed by using one-tailed χ2 statistics on collapsed SI-RPV data, comparing carriers and non-carriers in IBS patients compared with controls from ExAC. Results M-CAP/CADD combined analysis of all SI rare variants (N = 2146) resulted in the identification of 880 SI-RPVs with high predictive power (5% error rate for most variants). High-quality genotypes from IBS patients were available for 46 SI-RPVs, and 17 of these with at least 1 IBS carrier and ExAC reference data suitable for comparison were included in downstream association analyses (Table 1). We identified 88 IBS carriers (all single SI-RPV carriers; 3.99% of the entire cohort), with slightly higher prevalence in IBS-D (4.20%) and IBS-C (4.51%) than in other subtypes (Table 1). Compared with the large ethnically matched reference population from ExAC, most SI-RPVs occurred at higher frequency in IBS patients, and cumulative χ2 tests (carriers of any SI-RPVs vs non-carriers) demonstrated significant associations and consistent effects on IBS risk (Table 1). In a simulation experiment, 1 million permutations of ExAC data resampled to match case sample size resulted >99% of the times in identical findings (SI-RPV carriers more common in IBS than in ExAC; P < .001). Discussion We provide further evidence linking rare functionally deleterious SI variations to IBS susceptibility. Although the large ExAC reference population (chosen to ensure genotype representation) does not include data on bowel symptoms, the observed association may represent an underestimation of the true genetic risk effects; the global prevalence of IBS is near 11%, and a significant proportion of ExAC individuals might thus be affected, with potential for inflating the background SI-RPV’s carrier frequency among “controls” compared with an otherwise symptom-free reference group (type II error). The consistent observation of higher SI-RPV prevalence in IBS warrants further studies. This has the potential to identify groups among IBS patients for individualized management.

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

          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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            Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.

            SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.
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              Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.

              IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies.
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                Author and article information

                Journal
                101160775
                31839
                Clin Gastroenterol Hepatol
                Clin. Gastroenterol. Hepatol.
                Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
                1542-3565
                1542-7714
                27 June 2018
                21 February 2018
                October 2018
                01 October 2019
                : 16
                : 10
                : 1673-1676
                Affiliations
                [* ]Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain
                []Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
                [§ ]Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
                [|| ]Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
                []Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
                [# ]Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
                [** ]Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
                [‡‡ ]Lund University, Skåne University Hospital, Department of Internal Medicine, Lund, Sweden
                [§§ ]Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [|||| ]Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
                [¶¶ ]Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
                [## ]Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
                [*** ]S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy
                [‡‡‡ ]UOC Gastroenterologia, Padova University Hospital, Padova, Italy
                [§§§ ]Department of Medicine and Aging Sciences and CESI, G. D’Annunzio University and Foundation, Chieti, Italy
                [|||||| ]Department of Biomedical Sciences and Human Oncology (DIMO), Clinica Medica “A. Murri”, University of Bari Medical School, Bari, Italy
                [¶¶¶ ]Gastroenterology 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 Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
                [‡‡‡‡ ]Division of Gastroenterology, University of Michigan, Michigan Medicine, Ann Arbor, Michigan
                [§§§§ ]Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
                [|||||||| ]G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California
                [¶¶¶¶ ]Translational Research Center for Gastro Intestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
                [#### ]Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
                [***** ]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
                [‡‡‡‡‡ ]IKERBASQUE, Basque Science Foundation, Bilbao, Spain
                Author notes
                Address requests for reprints to: Mauro D’Amato, Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet T2, SE-17176 Stockholm, Sweden. mauro.damato@ 123456ki.se ; fax: +46-8-517 79304
                [a]

                Authors share co-first authorship.

                Article
                NIHMS977618
                10.1016/j.cgh.2018.01.047
                6103908
                29408290
                8af4d6fe-e743-4a97-bcd0-c48bcb676502

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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