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HLA variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).ORCID iD: 0000-0002-2152-4343
Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
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2022 (English)In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 15, no 5, p. 1249-1256, article id 13244Article in journal (Refereed) Published
Abstract [en]

The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease (IBD). Studies have demonstrated an increased risk in carriers of HLA-DQA1*02:01 and HLA-DRB1*07:01. We investigated whether these human leukocyte antigen (HLA) types were associated with azathioprine-induced pancreatitis also in Swedish patients with IBD, and whether the type of disease affected the association. Nineteen individuals with IBD who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n = 4891) and a control group matched for disease (n = 81). HLA-DQA1*02:01 and HLA-DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57-9.97], p = 0.0035) and matched controls (OR 3.55 [95% CI 1.23-10.98], p = 0.0275). In a disease-specific analysis, the correlation was positive in patients with Crohn's disease versus matched controls (OR 9.27 [95% CI 1.86-46.19], p = 0.0066), but not in those with ulcerative colitis versus matched controls (OR 0.69 [95% CI 0.07-6.74], p = 0.749). In patients with Crohn's disease, we estimated the conditional risk of carriers of HLA-DQA1*02:01-HLA-DRB1*07:01 to 7.3%, and the conditional risk of a non-carrier to 2.2%. We conclude that HLA-DQA1*02:01-HLA-DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn's disease.

Place, publisher, year, edition, pages
Wiley John Wiley & Sons, 2022. Vol. 15, no 5, p. 1249-1256, article id 13244
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-483675DOI: 10.1111/cts.13244ISI: 000757960600001PubMedID: 35120281OAI: oai:DiVA.org:uu-483675DiVA, id: diva2:1692326
Funder
Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 20170711Swedish Research Council, 2017-00641Swedish Research Council, 2021-00180Swedish Research Council, 2018-05973Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20170711Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Knut and Alice Wallenberg FoundationAvailable from: 2022-09-01 Created: 2022-09-01 Last updated: 2024-04-23Bibliographically approved
In thesis
1. Genomic Analysis of Adverse Drug Reactions
Open this publication in new window or tab >>Genomic Analysis of Adverse Drug Reactions
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adverse drug reactions (ADRs) pose a significant global challenge, leading to substantial costs, suffering, and even loss of life. Genetic factors can play a role in determining a patient's response to the drug treatments and predicting ADRs. While many genetic associations with ADRs have been identified, there are still numerous ADRs suspected to have genetic components.

In Paper I, the collection and curation strategies for ADR cases in the Swedegene biobank are established, presenting a cohort of 2,550 ADR-cases. Paper II presents the association between genetic variations in human leukocyte antigen (HLA) genes and the development of pancreatitis as a response to azathioprine treatment in patients with Crohn's disease. Paper III reports on an international collaboration to investigate the genetic aetiology of atypical femur fractures (AFF) during bisphosphonate treatment. The study found that previously identified genetic variants did not replicate, and --- as the cohort is the largest of its kind --- provides valuable insights into common genetic factors of AFF. Paper IV examines the genetic associations with central nervous system (CNS) toxicity as an ADR to antimicrobial drugs, identifying correlations with three genes linked to suicide and schizophrenia, although the biological connection remains unclear. Finally, Paper V presents a methodology for the experimental design of ADR studies by analysing the known protein interactions of drugs and proteins associated with ADRs. This approach aims to mitigate the impact of competing genetic correlations by identifying common protein interactions to validate the inclusion of drugs and ADRs in the study. These interactions are then ranked based on importance to the selected drugs and ADRs and used to propose genetic targets of interest. 

Overall, the findings of these studies contribute to the understanding of genetic predispositions to ADRs and provide a novel approach for data-driven experimental design for phenotype and genetic target selection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2055
Keywords
Adverse drug reactions, Genetic association, Network biology
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-527102 (URN)978-91-513-2139-4 (ISBN)
Public defence
2024-06-13, Rosénsalen, Akademiska sjukhuset, ing. 95/96, Uppsala, 13:00 (English)
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Available from: 2024-05-21 Created: 2024-04-23 Last updated: 2024-05-21

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Ås, JoelBertulyte, IlmaEriksson, NiclasWadelius, MiaHallberg, Pär

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