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Phenome of coeliac disease vs. inflammatory bowel disease.

ABSTRACT: Coeliac disease (CeD) is characterized by gliadin-induced intestinal inflammation appearing in genetically susceptible individuals, such as HLA-DQ2.5 carriers. CeD, as well as other chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis, has been associated with increased morbidity and mortality, but the causes are unknown. We systematically analysed CeD-associated diagnoses and compared them to conditions enriched in subjects with CD/UC as well as in HLA-DQ2.5 carriers without CeD. We compared the overall and cause-specific mortality and morbidity of 3,001 patients with CeD, 2,020 with CD, 4,399 with UC and 492,200 controls in the community-based UK Biobank. Disease-specific phenotypes were assessed with the multivariable Phenome Wide Association Study (PheWAS) method. Associations were adjusted for age, sex and body mass index. All disease groups displayed higher overall mortality than controls (CD: aHR = 1.91[1.70-2.17]; UC: aHR = 1.32 [1.20-1.46]; CeD: aHR = 1.38 [1.22-1.55]). Cardiovascular and cancer-related deaths were responsible for the majority of fatalities. PheWAS analysis revealed 166 Phecodes overrepresented in all three disorders, whereas only ~ 20% of enriched Phecodes were disease specific. Seven of the 58 identified CeD-specific Phecodes were enriched in individuals homozygous for HLA-DQ2.5 without diagnosed CeD. Four out of these seven Phecodes and eight out of 19 HLA-DQ2.5 specific Phecodes were more common in homozygous HLA-DQ2.5 subjects with vs. without CeD, highlighting the interplay between genetics and diagnosis-related factors. Our study illustrates that the morbidity and mortality in CeD share similarities with CD/UC, while the CeD-restricted conditions might be driven by both inherited and acquired factors.

SUBMITTER: Kleinjans M

PROVIDER: S-EPMC9418215 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Phenome of coeliac disease vs. inflammatory bowel disease.

Kleinjans Moritz M Schneider Carolin V CV Bruns Tony T Strnad Pavel P

Scientific reports 20220826 1

Coeliac disease (CeD) is characterized by gliadin-induced intestinal inflammation appearing in genetically susceptible individuals, such as HLA-DQ2.5 carriers. CeD, as well as other chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis, has been associated with increased morbidity and mortality, but the causes are unknown. We systematically analysed CeD-associated diagnoses and compared them to conditions enriched in subjects with CD/UC as well as in HLA-DQ2.5 carrier ...[more]

PMID: 36028550

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Project description:INTRODUCTION:Haemorheological and haemostatic changes predispose to the development of arterial and venous thrombotic events; however, limited information is available on the status of these changes in coeliac disease (CeD) and inflammatory bowel disease (IBD). In this study, we aim to describe the haemorheological and haemostatic profiles of CeD and IBD patients in a Hungarian cohort of patients to investigate whether any alterations contribute to elevated thrombotic risk. METHODS AND ANALYSIS:This is a case-control study involving newly diagnosed and followed CeD and IBD patients with age-matched and sex-matched non-CeD, non-IBD subjects with an allocation ratio of 1:1:1.After informed consent is obtained, a detailed medical history will be collected, including venous and arterial thrombotic risk factors and medications. Symptoms in CeD patients will be assessed with the Gastrointestinal Symptoms Rating Scale, and disease activity in IBD patients will be determined by disease-specific scores. Dietary adherence will be assessed among CeD patients with a thorough interview together with a measurement of self-reported adherence, dietary knowledge and urine analysis (detection of gluten immunogenic peptides). In addition to routine laboratory parameters, haemorheological (ie, erythrocyte deformability and aggregation, viscosity of whole blood and plasma) and haemostatic parameters (eg, protein C, protein S and antithrombin) with immunological indicators (ie, coeliac-specific serology and antiphospholipid antibodies) will be measured from venous blood for every participant.Primary and secondary outcomes will be haemorheological and haemostatic parameters, respectively. Univariate and multivariate statistics will be used to compare CeD and IBD patients to control subjects. Subgroup analysis will be performed by disease type in IBD, (Crohn's disease and ulcerose colitis), dietary adherence in CeD, and disease activity in IBD and CeD. ETHICS AND DISSEMINATION:The study was approved by the Regional and Local Research Ethics Committee, University of Pécs (Ref. No. 6917). Findings will be disseminated at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER:ISRCTN49677481.

Project description:Background: The molecular pathogenesis of small intestinal adenocarcinomas (SBA) is not well understood. Defining its molecular pathogenesis may lead us to better clinical interventions. Aim: to identify the molecular changes characteristic of SBA. Methods: Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations, by high resolution array comparative hybridization (aCGH), microsatellite status (MSI) and APC promoter methylation and mutation status. Furthermore, molecular alterations found in CD-related SBA were compared to non-CD related SBA. Results: Chromosomal changes were observed in 77% of the SBA. The most frequently (>10%) DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2 and 20p13-20q13.33 and losses of 4p13-4q35.2, 5q15-5q21.1 and 21p11.2-21q22.11. Seven highly amplified regions on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1 and 19q13.2 were also identified. CD-related and non CD-related SBA displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non CD-related and 73% CD-related SBA. No nonsense mutations were found. Last, 10% of the non CD-related SBA were MSI, whereas 43% of the CD-related SBA were MSI. Conclusions: Our study characterized specific chromosomal aberrations and amplifications involved in SBA pathogenesis. At the chromosomal level, CD-related and non CD-related SBA do not differ. The involvement of the MMR system in the pathogenesis of the CD-related SBA was larger than what has been observed in no CD-related SBA. No nonsense mutations were found in SBA, but frequent promoter methylation in CD-related SBA. Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations against a Human pool, by high resolution array comparative hybridization (aCGH),

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Phenome of coeliac disease vs. inflammatory bowel disease.

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Phenome of coeliac disease vs. inflammatory bowel disease.

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