. 2020 Oct 1;107(4):612-621.

doi: 10.1016/j.ajhg.2020.08.008. Epub 2020 Sep 3.

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

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, Affiliations

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.

PMID: 32888428
PMCID: PMC7536643
DOI: 10.1016/j.ajhg.2020.08.008

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

Kristi Krebs et al. Am J Hum Genet. 2020.

. 2020 Oct 1;107(4):612-621.

doi: 10.1016/j.ajhg.2020.08.008. Epub 2020 Sep 3.

Authors

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.

PMID: 32888428
PMCID: PMC7536643
DOI: 10.1016/j.ajhg.2020.08.008

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.

PubMed Disclaimer

Conflict of interest statement

C.M.L. has collaborated with Novo Nordisk and Bayer in research, and in accordance with a university agreement, did not accept any personal payment. W.W., A.A., and members of the 23andMe Research Team are employed by and hold stock or stock options in 23andMe, Inc. There were no other relationships or activities that could appear to have influenced the submitted work. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or the NIH.

Figures

**Figure 1**
Manhattan Plot and HLA Locus of the Genome-wide Association Study of Penicillin Allergy The X axes indicate chromosomal positions and Y axes −log₁₀ of the p Values. (A) Each dot represents a single-nucleotide polymorphism (SNP). The dotted line indicates the genome-wide significance (p value < 5.0 × 10⁻⁸) p value threshold. (B) SNPs are colored according to their linkage disequilibrium (LD; based on the 1000 Genomes phase3 EUR reference panel) with the lead SNP. The SNP marked with a purple diamond is the lead SNP rs114892859.

**Figure 2**
HLA-B^∗55:01 Allele Association with Self-Reported Penicillin Allergy The odds ratios (dots) and 95% confidence intervals (CI, horizontal lines) for the association of the HLA allele with penicillin allergy are presented. The plot is annotated with p values and case-control numbers. Color coding indicates the results for discovery cohorts UKBB (black), EstBB (blue), and BioVU (purple) and replication results of the HLA-B^∗55:01 allele in the 23andMe research cohort (green). Results of the meta-analysis of all four cohorts is indicated with a diamond (red). Self-reported penicillin allergy is defined as ICD10 code Z88.0 (UKBB), reported drug allergy labels from the allergy section of the EHR (BioVU), reported allergy to drugs in ATC J01C^∗ class (EstBB), or reported allergy to penicillin (23andMe).

See this image and copyright information in PMC

References

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

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