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Genomic Analysis of Adverse Drug Reactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.ORCID iD: 0000-0001-8687-0629
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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 [en]
Adverse drug reactions, Genetic association, Network biology
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-527102ISBN: 978-91-513-2139-4 (print)OAI: oai:DiVA.org:uu-527102DiVA, id: diva2:1853890
Public defence
2024-06-13, Rosénsalen, Akademiska sjukhuset, ing. 95/96, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2024-05-21 Created: 2024-04-23 Last updated: 2024-05-21
List of papers
1. Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
Open this publication in new window or tab >>Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
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2024 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 19, no 2, article id e0299075Article in journal (Refereed) Published
Abstract [en]

A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2024
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-526190 (URN)10.1371/journal.pone.0299075 (DOI)001181714500084 ()38422004 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, NP:00085Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Science for Life Laboratory, SciLifeLab
Available from: 2024-04-05 Created: 2024-04-05 Last updated: 2024-04-23Bibliographically approved
2. HLA variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease
Open this publication in new window or tab >>HLA variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease
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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
John Wiley & SonsWiley, 2022
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-483675 (URN)10.1111/cts.13244 (DOI)000757960600001 ()35120281 (PubMedID)
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 Foundation
Available from: 2022-09-01 Created: 2022-09-01 Last updated: 2024-04-23Bibliographically approved
3. SWEDEGENE: a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions
Open this publication in new window or tab >>SWEDEGENE: a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions
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2020 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, no 4, p. 579-585Article in journal (Refereed) Published
Abstract [en]

SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-425656 (URN)10.1038/s41397-020-0148-3 (DOI)000508151600001 ()31949290 (PubMedID)
Funder
Swedish Research Council, 2017-00641Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Science for Life Laboratory - a national resource center for high-throughput molecular bioscience, NP00085Erik, Karin och Gösta Selanders FoundationThuréus stiftelse för främjande av geriatrisk forskningRegion StockholmKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)
Available from: 2020-11-23 Created: 2020-11-23 Last updated: 2024-04-23Bibliographically approved
4. Gene-based association analysis of a large patient cohort identifies potential genecandidates for atypical femur fractures
Open this publication in new window or tab >>Gene-based association analysis of a large patient cohort identifies potential genecandidates for atypical femur fractures
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:

Several small genetic association studies have been conducted for atypical femurfracture (AFF) without replication of results. We assessed previously implicated and novel genesassociated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES).

Methods:

We performed gene-based association analysis on 139 European AFF cases and 196 controlsmatched for bisphosphonate use. We tested all rare, protein-altering variants using both candidategene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs(uncorrected p-values < 0.01) were investigated in a Swedish whole-genome sequencing replicationstudy and assessed in 46 non-European cases.

Results:

In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-freeapproach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likelycandidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in thereplication analysis, albeit not statistically significant. Three SNPs associated with SORD expressionaccording to the GTEx portal, were in linkage disequilibrium (R2 ≥0.2) with a SNP previouslyreported in a genome-wide association study of AFF. The prevalence of carriers of variants for bothPLOD2 and SORD was higher in Asian versus European cases.

Conclusions:

While we did not identify genes enriched for damaging variants, we found suggestiveevidence of a role for XRN2, PLOD2 and SORD, which requires further investigation. Our findingsindicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The studyprovides a stepping-stone for future larger genetic studies of AFF.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-526953 (URN)
Available from: 2024-04-20 Created: 2024-04-20 Last updated: 2024-04-23
5. Network-Based Analysis of Protein Interactions among Drugs and Adverse Reactions: Identifying Phenotype-Groupings and Key Genes
Open this publication in new window or tab >>Network-Based Analysis of Protein Interactions among Drugs and Adverse Reactions: Identifying Phenotype-Groupings and Key Genes
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:

Adverse drug reactions (ADRs) present a significant healthcare challenge, leading to morbidity, hospitalizations, and even fatalities. Serious ADRs are in general infrequent, since drugs with a high risk-benefit ratio are rarely approved by the authorities.Genetic factors contribute to serious ADRs, driving pharmacogenomic research to investigate drug-ADR-genetic relationships. These relationships are, however, still largely unstudied due to the scarcity of cases. This scarcity, coupled with the multiple hypothesis problem of genetic studies, poses challenges for these studies. One approach is to group similar ADRs or drugs to bolster sample sizes. However, grouping of drugs and ADRs requires caution to avoid including biologically ill-fitting cases. The objective of our study is to cluster drugs and ADRs based on previous genetic associations and shared protein interactions to propose phenotype groups and genetic targets for investigation.

Methods:

We developed a Bayesian probability model to substantiate protein-protein interactions across different drugs or ADRs. Subsequently, these proximity values were utilised for spectral clustering to form phenotype-groups. Once obtained, the model was reformulated to rank shared proteins for each cluster.

Results:Permutation analysis demonstrated high sensitivity in correctly clustering drugs into therapeutic groups (sensitivity 94-97%) - outperforming other proposed methods - and assigning ADRs to clusters (sensitivity 86%). The model's reformulation enabled the ranking of shared proteins within each cluster, revealing enrichment in KEGG pathways relevant to therapeutic classifications. 

Discussion:

This method successfully replicated known therapeutic drug classifications with high sensitivity, using shared protein interactions among KEGG pathways associated with drug functions. Using the proximity score and spectral clustering we propose phenotype groups and genetic targets for investigations. However, further studies are needed to assess the method's utility for the selection of cases and for target identification in less homogeneous drug-ADR scenarios.

Keywords
Adverse drug reactions; target discovery; study design; protein-protein interaction; statistical modelling; enrichment analysis
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-526952 (URN)
Available from: 2024-04-20 Created: 2024-04-20 Last updated: 2024-04-29

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