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The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register.
Shrestha, S, Olén, O, Eriksson, C, Everhov, ÅH, Myrelid, P, Visuri, I, Ludvigsson, JF, Schoultz, I, Montgomery, S, Sachs, MC, et al
Scandinavian journal of gastroenterology. 2020;(4):430-435
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Abstract
Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown.Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals.Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis.Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström, M, Diekmann, L, Bonfiglio, F, Hadizadeh, F, Kuech, EM, von Köckritz-Blickwede, M, Thingholm, LB, Zheng, T, Assadi, G, Dierks, C, et al
Gut. 2018;67(2):263-270
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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 (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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Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.
Garcia-Etxebarria, K, Zheng, T, Bonfiglio, F, Bujanda, L, Dlugosz, A, Lindberg, G, Schmidt, PT, Karling, P, Ohlsson, B, Simren, M, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(10):1673-1676
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).
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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.
Bonfiglio, F, Zheng, T, Garcia-Etxebarria, K, Hadizadeh, F, Bujanda, L, Bresso, F, Agreus, L, Andreasson, A, Dlugosz, A, Lindberg, G, et al
Gastroenterology. 2018;(1):168-179
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Abstract
BACKGROUND & AIMS Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M.
Henström, M, Hadizadeh, F, Beyder, A, Bonfiglio, F, Zheng, T, Assadi, G, Rafter, J, Bujanda, L, Agreus, L, Andreasson, A, et al
Gut. 2017;(9):1725-1727
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Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study.
Racine, A, Carbonnel, F, Chan, SS, Hart, AR, Bueno-de-Mesquita, HB, Oldenburg, B, van Schaik, FD, Tjønneland, A, Olsen, A, Dahm, CC, et al
Inflammatory bowel diseases. 2016;(2):345-54
Abstract
BACKGROUND Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn's disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks. METHODS Within the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case-control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis. RESULTS No dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a "high sugar and soft drinks" pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00-2.82]; Ptrend = 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes. CONCLUSIONS A diet imbalance with high consumption of sugar and soft drinks and low consumption of vegetables was associated with UC risk. Further studies are needed to investigate whether microbiota alterations or other mechanisms mediate this association.
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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.
Ek, WE, Reznichenko, A, Ripke, S, Niesler, B, Zucchelli, M, Rivera, NV, Schmidt, PT, Pedersen, NL, Magnusson, P, Talley, NJ, et al
Gut. 2015;(11):1774-82
Abstract
OBJECTIVE 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. DESIGN We conducted a GWA study (GWAS) of IBS in a general population sample of 11,326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.
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Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
Beyder, A, Mazzone, A, Strege, PR, Tester, DJ, Saito, YA, Bernard, CE, Enders, FT, Ek, WE, Schmidt, PT, Dlugosz, A, et al
Gastroenterology. 2014;(7):1659-1668
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Abstract
BACKGROUND & AIMS 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. METHODS We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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Association between high dietary intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid and reduced risk of Crohn's disease.
Chan, SS, Luben, R, Olsen, A, Tjonneland, A, Kaaks, R, Lindgren, S, Grip, O, Bergmann, MM, Boeing, H, Hallmans, G, et al
Alimentary pharmacology & therapeutics. 2014;(8):834-42
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Abstract
BACKGROUND There are plausible mechanisms for how dietary docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, could prevent Crohn's disease (CD). AIM: To conduct a prospective study to investigate the association between increased intake of DHA and risk of CD. METHODS Overall, 229 702 participants were recruited from nine European centres between 1991 and 1998. At recruitment, dietary intakes of DHA and fatty acids were measured using validated food frequency questionnaires. The cohort was monitored through to June 2004 to identify participants who developed incident CD. In a nested case-control analysis, each case was matched with four controls; odds ratios (ORs) were calculated for quintiles of DHA intake, adjusted for total energy intake, smoking, other dietary fatty acids, dietary vitamin D and body mass index. RESULTS Seventy-three participants developed incident CD. All higher quintiles of DHA intake were inversely associated with development of CD; the highest quintile had the greatest effect size (OR = 0.07; 95% CI = 0.02-0.81). The OR trend across quintiles of DHA was 0.54 (95% CI = 0.30-0.99, Ptrend = 0.04). Including BMI in the multivariate analysis, due to its correlation with dietary fat showed similar associations. There were no associations with the other dietary fatty acids studied. CONCLUSION There were inverse associations, with a biological gradient between increasing dietary docosahexaenoic acid intakes and incident Crohn's disease. Further studies in other populations should measure docosahexaenoic acid to determine if the association is consistent and the hypothesis tested in randomised controlled trials of purely docosahexaenoic acid supplementation.