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Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy

View ORCID ProfileKristi Krebs, View ORCID ProfileJonas Bovijn, View ORCID ProfileMaarja Lepamets, View ORCID ProfileJenny C Censin, Tuuli Jürgenson, Dage Särg, View ORCID ProfileYang Luo, View ORCID ProfileLine Skotte, View ORCID ProfileFrank Geller, View ORCID ProfileBjarke Feenstra, Wei Wang, View ORCID ProfileAdam Auton, 23andMe Research Team, View ORCID ProfileSoumya Raychaudhuri, View ORCID ProfileTõnu Esko, View ORCID ProfileAndres Metspalu, Sven Laur, View ORCID ProfileMichael V Holmes, View ORCID ProfileCecilia M Lindgren, View ORCID ProfileReedik Mägi, View ORCID ProfileLili Milani, View ORCID ProfileJoão Fadista
doi: https://doi.org/10.1101/2020.02.27.967497
Kristi Krebs
1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
2Institute of Molecular and Cell Biology, University of Tartu, Tartu, Riia 23, 51010, Estonia
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Jonas Bovijn
3Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom
4Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7FZ, United Kingdom
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Maarja Lepamets
1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
2Institute of Molecular and Cell Biology, University of Tartu, Tartu, Riia 23, 51010, Estonia
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Jenny C Censin
3Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom
4Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7FZ, United Kingdom
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Tuuli Jürgenson
5Institute of Mathematics and Statistics, University of Tartu
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Dage Särg
6Institute of Computer Science, University of Tartu, Tartu, Estonia
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Yang Luo
7Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
8Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
9Broad Institute of MIT and Harvard, Cambridge, MA, USA
10Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
11Center for Data Sciences, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Line Skotte
12Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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Frank Geller
12Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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Bjarke Feenstra
12Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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Wei Wang
1323andMe, Inc., Sunnyvale, CA, USA
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Adam Auton
1323andMe, Inc., Sunnyvale, CA, USA
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Soumya Raychaudhuri
7Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
8Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
9Broad Institute of MIT and Harvard, Cambridge, MA, USA
10Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
11Center for Data Sciences, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
14Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
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Tõnu Esko
1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Andres Metspalu
1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Sven Laur
6Institute of Computer Science, University of Tartu, Tartu, Estonia
15STACC, Tartu, Estonia
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Michael V Holmes
4Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7FZ, United Kingdom
16National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
17Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, United Kingdom
18Medical Research Council Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, United Kingdom
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Cecilia M Lindgren
3Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom
4Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7FZ, United Kingdom
16National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
19Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
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Reedik Mägi
1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Lili Milani
1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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  • For correspondence: lili.milani@ut.ee
João Fadista
12Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
20Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
21Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Abstract

Background Hypersensitivity reactions to drugs are often unpredictable and can be life-threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown.

Methods We extracted data from the electronic health records of 52,000 Estonian and 500,000 UK biobank participants to study the role of genetic variation in the occurrence of penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from up to 22,554 and 488,377 individuals from the Estonian and UK cohorts, respectively, to further fine-map the human leukocyte antigen (HLA) association and replicated our results in two additional cohorts involving a total of 1.14 million individuals.

Results Genome-wide meta-analysis of penicillin allergy revealed a significant association located in the HLA region on chromosome 6. The signal was further fine-mapped to the HLA-B*55:01 allele (OR 1.47 95% CI 1.37-1.58, P-value 4.63×10-26) and confirmed by independent replication in two cohorts. The meta-analysis of all four cohorts in the study revealed a strong association of HLA-B*55:01 allele with penicillin allergy (OR 1.33 95% CI 1.29-1.37, P-value 2.23×10-72). In silico follow-up suggests a potential effect on T lymphocytes at HLA-B*55:01.

Conclusion We present the first robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

Footnotes

  • Author name corrected and few grammatical corrections.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 02, 2020.
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Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy
Kristi Krebs, Jonas Bovijn, Maarja Lepamets, Jenny C Censin, Tuuli Jürgenson, Dage Särg, Yang Luo, Line Skotte, Frank Geller, Bjarke Feenstra, Wei Wang, Adam Auton, 23andMe Research Team, Soumya Raychaudhuri, Tõnu Esko, Andres Metspalu, Sven Laur, Michael V Holmes, Cecilia M Lindgren, Reedik Mägi, Lili Milani, João Fadista
bioRxiv 2020.02.27.967497; doi: https://doi.org/10.1101/2020.02.27.967497
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Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy
Kristi Krebs, Jonas Bovijn, Maarja Lepamets, Jenny C Censin, Tuuli Jürgenson, Dage Särg, Yang Luo, Line Skotte, Frank Geller, Bjarke Feenstra, Wei Wang, Adam Auton, 23andMe Research Team, Soumya Raychaudhuri, Tõnu Esko, Andres Metspalu, Sven Laur, Michael V Holmes, Cecilia M Lindgren, Reedik Mägi, Lili Milani, João Fadista
bioRxiv 2020.02.27.967497; doi: https://doi.org/10.1101/2020.02.27.967497

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