Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy

Kristi Krebs; Jonas Bovijn; Neil Zheng; Maarja Lepamets; Jenny C Censin; Tuuli Jürgenson; Dage Särg; Erik Abner; Triin Laisk; Yang Luo; Line Skotte; Frank Geller; Bjarke Feenstra; Wei Wang; Adam Auton; 23andMe Research Team; Soumya Raychaudhuri; Tõnu Esko; Andres Metspalu; Sven Laur; Dan M Roden; Wei-Qi Wei; Michael V Holmes; Cecilia M Lindgren; Elizabeth J Phillips; Reedik Mägi; Lili Milani; João Fadista

doi:10.1016/j.ajhg.2020.08.008

Genome-wide Study Identifies Association between HLA-B^∗55:01 and Self-Reported Penicillin Allergy

Am J Hum Genet. 2020 Oct 1;107(4):612-621. doi: 10.1016/j.ajhg.2020.08.008. Epub 2020 Sep 3.

Authors

Kristi Krebs¹, Jonas Bovijn², Neil Zheng³, Maarja Lepamets¹, Jenny C Censin², Tuuli Jürgenson⁴, Dage Särg⁵, Erik Abner⁴, Triin Laisk⁴, Yang Luo⁶, Line Skotte⁷, Frank Geller⁷, Bjarke Feenstra⁷, Wei Wang⁸, Adam Auton⁸; 23andMe Research Team⁸; Soumya Raychaudhuri⁹, Tõnu Esko⁴, Andres Metspalu⁴, Sven Laur¹⁰, Dan M Roden¹¹, Wei-Qi Wei³, Michael V Holmes¹², Cecilia M Lindgren¹³, Elizabeth J Phillips¹⁴, Reedik Mägi⁴, Lili Milani¹⁵, João Fadista¹⁶

Collaborators

23andMe Research Team:
Michelle Agee, Stella Aslibekyan, Robert K Bell, Katarzyna Bryc, Sarah K Clark, Sarah L Elson, Kipper Fletez-Brant, Pierre Fontanillas, Nicholas A Furlotte, Pooja M Gandhi, Karl Heilbron, Barry Hicks, David A Hinds, Karen E Huber, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Marie K Luff, Jennifer C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Sahar V Mozaffari, Priyanka Nandakumar, Elizabeth S Noblin, Carrie A M Northover, Jared O'Connell, Aaron A Petrakovitz, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Anjali J Shastri, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Robert J Tunney, Vladimir Vacic, Xin Wang, Amir S Zare

Affiliations

¹ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
² Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
⁵ Institute of Computer Science, University of Tartu, Tartu 51009, Estonia.
⁶ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark.
⁸ 23andMe, Inc., Sunnyvale, CA 94086, USA.
⁹ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK.
¹⁰ Institute of Computer Science, University of Tartu, Tartu 51009, Estonia; STACC, Tartu 51009, Estonia.
¹¹ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, TN 37232, USA.
¹² Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 7LE, UK; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK; Medical Research Council Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
¹³ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 7LE, UK; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
¹⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, TN 37232, USA; Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia.
¹⁵ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia. Electronic address: lili.milani@ut.ee.
¹⁶ Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark; Department of Clinical Sciences, Lund University Diabetes Centre, 214 28 Malmö, Sweden; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.

Abstract

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. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B^∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10^-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10^-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B^∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

Keywords: 23andMe; BioVu; EHR; EstBB; GWAS; HLA-B∗55:01; PTPN22; UKBB; penicillin allergy; pharmacogenomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Arthritis, Rheumatoid / complications
Arthritis, Rheumatoid / genetics*
Arthritis, Rheumatoid / immunology
Chromosomes, Human, Pair 6 / chemistry
Drug Hypersensitivity / complications
Drug Hypersensitivity / etiology
Drug Hypersensitivity / genetics*
Drug Hypersensitivity / immunology
Electronic Health Records
Europe
Female
Gene Expression
Genetic Loci
Genetic Predisposition to Disease
Genome, Human
Genome-Wide Association Study
HLA-B Antigens / genetics*
HLA-B Antigens / immunology
Histocompatibility Testing
Humans
Male
Penicillins / adverse effects
Polymorphism, Single Nucleotide*
Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics*
Protein Tyrosine Phosphatase, Non-Receptor Type 22 / immunology
Psoriasis / complications
Psoriasis / genetics*
Psoriasis / immunology
Self Report
T-Lymphocytes / immunology
T-Lymphocytes / pathology
United States

Substances

HLA-B Antigens
HLA-B55 antigen
Penicillins
PTPN22 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 22

Abstract

Publication types

MeSH terms

Substances

Grants and funding