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Attelind, S., Eriksson, N., Sundstroem, A., Wadelius, M. & Hallberg, P. (2023). Identification of risk factors for adverse drug reactions in a pharmacovigilance database. Pharmacoepidemiology and Drug Safety, 32(12), 1431-1438
Open this publication in new window or tab >>Identification of risk factors for adverse drug reactions in a pharmacovigilance database
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2023 (English)In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 32, no 12, p. 1431-1438Article in journal (Refereed) Published
Abstract [en]

Introduction In addition to identifying new safety signals, pharmacovigilance databases could be used to identify potential risk factors for adverse drug reactions (ADRs).Objective To evaluate whether data mining in a pharmacovigilance database can be used to identify known and possible novel risk factors for ADRs, for use in pharmacovigilance practice.Method Exploratory data mining was performed within the Swedish national database of spontaneously reported ADRs. Bleeding associated with direct oral anticoagulants (DOACs)-rivaroxaban, apixaban, edoxaban, and dabigatran-was used as a test model. We compared demographics, drug treatment, and clinical features between cases with bleeding (N = 965) and controls who had experienced other serious ADRs to DOACs (N = 511). Statistical analysis was performed by unadjusted and age adjusted logistic regression models, and the random forest based machine-learning method Boruta.Results In the logistic regression, 13 factors were significantly more common among cases of bleeding compared with controls. Eleven were labelled or previously proposed risk factors. Cardiac arrhythmia (e.g., atrial fibrillation), hypertension, mental impairment disorders (e.g., dementia), renal and urinary tract procedures, gastrointestinal ulceration and perforation, and interacting drugs remained significant after adjustment for age. In the Boruta analysis, high age, arrhythmia, hypertension, cardiac failure, thromboembolism, and pharmacodynamically interacting drugs had a larger than random association with the outcome. High age, cardiac arrhythmia, hypertension, cardiac failure, and pharmacodynamically interacting drugs had odds ratios for bleeding above one, while thromboembolism had an odds ratio below one.Conclusions We demonstrated that data mining within a pharmacovigilance database identifies known risk factors for DOAC bleeding, and potential risk factors such as dementia and atrial fibrillation. We propose that the method could be used in pharmacovigilance for identification of potential ADR risk factors that merit further evaluation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
anticoagulant-induced bleedings, direct oral anticoagulants, pharmacovigilance database, risk factors, suspected adverse drug reactions
National Category
Cardiac and Cardiovascular Systems Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-522417 (URN)10.1002/pds.5679 (DOI)001049818600001 ()37580910 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20200777EU, Horizon 2020
Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Ollila, H. M., Sharon, E., Lin, L., Sinnott-Armstrong, N., Ambati, A., Yogeshwar, S. M., . . . Mignot, E. J. (2023). Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature Communications, 14, Article ID 2709.
Open this publication in new window or tab >>Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 2709Article in journal (Refereed) Published
Abstract [en]

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R).

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Immunology in the medical area Neurosciences
Identifiers
urn:nbn:se:uu:diva-507041 (URN)10.1038/s41467-023-36120-z (DOI)000994445900002 ()37188663 (PubMedID)
Funder
Swedish Medical Products Agency
Available from: 2023-07-04 Created: 2023-07-04 Last updated: 2023-07-04Bibliographically approved
Attelind, S., Hallberg, P., Wadelius, M., Hamberg, A.-K., Siegbahn, A., Granger, C. B., . . . Eriksson, N. (2022). Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events. Frontiers in Genetics, 13, Article ID 982955.
Open this publication in new window or tab >>Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
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2022 (English)In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 13, article id 982955Article in journal (Refereed) Published
Abstract [en]

Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59-243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
factor Xa inhibitors, apixaban, atrial fibrillation, genome-wide association study, pharmacokinetics, pharmacogenetics, drug-related side effects and adverse reactions
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-486690 (URN)10.3389/fgene.2022.982955 (DOI)000861877900001 ()36186466 (PubMedID)
Funder
Swedish Foundation for Strategic Research, RB13-0197Swedish Heart Lung Foundation, 20200777The Swedish Brain Foundation, FO 2020-0234The Swedish Stroke AssociationErik, Karin och Gösta Selanders Foundation
Available from: 2022-10-17 Created: 2022-10-17 Last updated: 2023-02-23Bibliographically approved
Cavalli, M., Eriksson, N., Karlsson Sundbaum, J., Wallenberg, M., Kohnke, H., Baecklund, E., . . . Wadelius, M. (2022). Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate. Pharmacogenomics (London), 23(15), 813-820
Open this publication in new window or tab >>Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate
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2022 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 23, no 15, p. 813-820Article in journal (Refereed) Published
Abstract [en]

Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 x 10(-8)) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 x ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.

Place, publisher, year, edition, pages
Future Medicine Ltd, 2022
Keywords
adverse reactions, drug-related side effects, genome-wide association study, hepatotoxicity, methotrexate, pharmacogenetics, rheumatoid arthritis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-491220 (URN)10.2217/pgs-2022-0074 (DOI)000850598700001 ()36070248 (PubMedID)
Funder
Swedish 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, 20170711
Available from: 2022-12-20 Created: 2022-12-20 Last updated: 2022-12-20Bibliographically approved
Ås, J., Bertulyte, I., Eriksson, N., Magnusson, P. K. E., Wadelius, M. & Hallberg, P. (2022). HLA variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease. Clinical and Translational Science, 15(5), 1249-1256, Article ID 13244.
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: 2024-01-15Bibliographically approved
Mathey, C. M., Maj, C., Scheer, A. B., Fazaal, J., Wedi, B., Wieczorek, D., . . . Forstner, A. J. (2022). Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes. Frontiers in Genetics, 13, Article ID 914376.
Open this publication in new window or tab >>Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
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2022 (English)In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 13, article id 914376Article in journal (Refereed) Published
Abstract [en]

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
angioedema, angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, genetics, hereditary angioedema, sequencing
National Category
Medical and Health Sciences Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-491743 (URN)10.3389/fgene.2022.914376 (DOI)000891708900001 ()35923707 (PubMedID)
Available from: 2022-12-22 Created: 2022-12-22 Last updated: 2023-04-14Bibliographically approved
Ghouse, J., Ahlberg, G., Andreasen, L., Banasi, K., Brunak, S., Schwinn, M., . . . Olesen, M. S. (2021). Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors. Journal of the American College of Cardiology, 78(7), 696-709
Open this publication in new window or tab >>Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors
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2021 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 78, no 7, p. 696-709Article in journal (Refereed) Published
Abstract [en]

BACKGROUND Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensinconverting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors #180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI:-0.83 to-0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI:-0.46 to-0.05; P = 0.013) blood pressure. CONCLUSIONS In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema. 

Place, publisher, year, edition, pages
ElsevierElsevier BV, 2021
Keywords
ACE inhibitors, ADR, angioedema, bradykinin, adverse drug&nbsp, reaction, bradykinin&nbsp, receptor B < sub > 2 <, sub >
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-451732 (URN)10.1016/j.jacc.2021.05.054 (DOI)000684836000008 ()34384552 (PubMedID)
Funder
NordForskSwedish 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, 20170711Swedish Research Council, 2017-00641
Available from: 2021-08-31 Created: 2021-08-31 Last updated: 2024-01-15Bibliographically approved
Karlsson Sundbaum, J., Baecklund, E., Eriksson, N., Kohnke, H., Wallenberg, M., Cavalli, M., . . . Hallberg, P. (2021). Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate. Pharmacogenomics (London), 22(15), 973-982
Open this publication in new window or tab >>Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate
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2021 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 22, no 15, p. 973-982Article in journal (Refereed) Published
Abstract [en]

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

Place, publisher, year, edition, pages
Future Medicine, 2021
Keywords
cohort study, genome-wide association studies, hepatotoxicity, methotrexate, rheumatoid arthritis, risk 13 factors
National Category
Clinical Laboratory Medicine Rheumatology and Autoimmunity
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-462628 (URN)10.2217/pgs-2021-0064 (DOI)000695859000001 ()34521259 (PubMedID)
Funder
Swedish Research Council, 2018-03307Swedish Research Council, 521-20112440Swedish Research Council, 521-2014-3370Diabetesfonden, DIA2017-269Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Agnes and Mac Rudberg FoundationGurli och Edward Brunnbergs stiftelse för reumatologisk forskningErik, Karin och Gösta Selanders FoundationSwedish Rheumatism Association
Available from: 2021-12-28 Created: 2021-12-28 Last updated: 2024-01-15Bibliographically approved
Maroteau, C., Siddiqui, M. K., Veluchamy, A., Carr, F., White, M., Cassidy, A. J., . . . Palmer, C. N. A. (2020). Exome sequencing reveals common and rare variants in F5 associated with ACE inhibitor and angiotensin receptor blocker-induced angioedema. Clinical Pharmacology and Therapeutics, 108(6), 1195-1202
Open this publication in new window or tab >>Exome sequencing reveals common and rare variants in F5 associated with ACE inhibitor and angiotensin receptor blocker-induced angioedema
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2020 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 108, no 6, p. 1195-1202Article in journal (Refereed) Published
Abstract [en]

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reactionto angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysisof five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10−3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-427119 (URN)10.1002/cpt.1927 (DOI)000549508700001 ()32496628 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602108Swedish 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, 20170711Knut and Alice Wallenberg FoundationSwedish Research Council, 2017-00641
Available from: 2020-12-16 Created: 2020-12-16 Last updated: 2023-03-31Bibliographically approved
Rasmussen, E. R., Hallberg, P., Baranova, E. V., Eriksson, N., Karawajczyk, M., Johansson, C., . . . Wadelius, M. (2020). Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.. The Pharmacogenomics Journal, 20(6), 770-783
Open this publication in new window or tab >>Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
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2020 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, no 6, p. 770-783Article in journal (Refereed) Published
Abstract [en]

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-431729 (URN)10.1038/s41397-020-0165-2 (DOI)000514761400001 ()32080354 (PubMedID)
Available from: 2021-01-15 Created: 2021-01-15 Last updated: 2021-06-23Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3465-3280

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