PMID- 32888428
OWN - NLM
STAT- MEDLINE
DCOM- 20201130
LR  - 20240216
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 107
IP  - 4
DP  - 2020 Oct 1
TI  - Genome-wide Study Identifies Association between HLA-B( *)55:01 and Self-Reported 
      Penicillin Allergy.
PG  - 612-621
LID - S0002-9297(20)30276-7 [pii]
LID - 10.1016/j.ajhg.2020.08.008 [doi]
AB  - 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 x 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 x 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.
CI  - Copyright (c) 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Krebs, Kristi
AU  - Krebs K
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 
      51010, Estonia.
FAU - Bovijn, Jonas
AU  - Bovijn J
AD  - 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.
FAU - Zheng, Neil
AU  - Zheng N
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, TN 37232, USA.
FAU - Lepamets, Maarja
AU  - Lepamets M
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 
      51010, Estonia.
FAU - Censin, Jenny C
AU  - Censin JC
AD  - 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.
FAU - Jurgenson, Tuuli
AU  - Jurgenson T
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia.
FAU - Sarg, Dage
AU  - Sarg D
AD  - Institute of Computer Science, University of Tartu, Tartu 51009, Estonia.
FAU - Abner, Erik
AU  - Abner E
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia.
FAU - Laisk, Triin
AU  - Laisk T
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia.
FAU - Luo, Yang
AU  - Luo Y
AD  - 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.
FAU - Skotte, Line
AU  - Skotte L
AD  - Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, 
      Denmark.
FAU - Geller, Frank
AU  - Geller F
AD  - Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, 
      Denmark.
FAU - Feenstra, Bjarke
AU  - Feenstra B
AD  - Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, 
      Denmark.
FAU - Wang, Wei
AU  - Wang W
AD  - 23andMe, Inc., Sunnyvale, CA 94086, USA.
FAU - Auton, Adam
AU  - Auton A
AD  - 23andMe, Inc., Sunnyvale, CA 94086, USA.
CN  - 23andMe Research Team
AD  - 23andMe, Inc., Sunnyvale, CA 94086, USA.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AD  - 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.
FAU - Esko, Tonu
AU  - Esko T
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia.
FAU - Metspalu, Andres
AU  - Metspalu A
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia.
FAU - Laur, Sven
AU  - Laur S
AD  - Institute of Computer Science, University of Tartu, Tartu 51009, Estonia; STACC, 
      Tartu 51009, Estonia.
FAU - Roden, Dan M
AU  - Roden DM
AD  - 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.
FAU - Wei, Wei-Qi
AU  - Wei WQ
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, TN 37232, USA.
FAU - Holmes, Michael V
AU  - Holmes MV
AD  - 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.
FAU - Lindgren, Cecilia M
AU  - Lindgren CM
AD  - 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.
FAU - Phillips, Elizabeth J
AU  - Phillips EJ
AD  - 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.
FAU - Magi, Reedik
AU  - Magi R
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia.
FAU - Milani, Lili
AU  - Milani L
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, 
      Estonia. Electronic address: lili.milani@ut.ee.
FAU - Fadista, Joao
AU  - Fadista J
AD  - Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, 
      Denmark; Department of Clinical Sciences, Lund University Diabetes Centre, 214 28 
      Malmo, Sweden; Institute for Molecular Medicine Finland (FIMM), University of 
      Helsinki, Helsinki 00014, Finland.
LA  - eng
GR  - P50 HD028138/HD/NICHD NIH HHS/United States
GR  - UL1 TR000445/TR/NCATS NIH HHS/United States
GR  - R01 GM139891/GM/NIGMS NIH HHS/United States
GR  - R01 HG010863/HG/NHGRI NIH HHS/United States
GR  - R01 AI152183/AI/NIAID NIH HHS/United States
GR  - U01 AI154659/AI/NIAID NIH HHS/United States
GR  - R01 HL133786/HL/NHLBI NIH HHS/United States
GR  - P50 GM115305/GM/NIGMS NIH HHS/United States
GR  - R21 AI139021/AI/NIAID NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200903
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B55 antigen)
RN  - 0 (Penicillins)
RN  - EC 3.1.3.48 (PTPN22 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 22)
SB  - IM
MH  - Adult
MH  - Alleles
MH  - Arthritis, Rheumatoid/complications/*genetics/immunology
MH  - Chromosomes, Human, Pair 6/chemistry
MH  - Drug Hypersensitivity/complications/etiology/*genetics/immunology
MH  - Electronic Health Records
MH  - Europe
MH  - Female
MH  - Gene Expression
MH  - Genetic Loci
MH  - Genetic Predisposition to Disease
MH  - Genome, Human
MH  - Genome-Wide Association Study
MH  - HLA-B Antigens/*genetics/immunology
MH  - Histocompatibility Testing
MH  - Humans
MH  - Male
MH  - Penicillins/adverse effects
MH  - *Polymorphism, Single Nucleotide
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 22/*genetics/immunology
MH  - Psoriasis/complications/*genetics/immunology
MH  - Self Report
MH  - T-Lymphocytes/immunology/pathology
MH  - United States
PMC - PMC7536643
OTO - NOTNLM
OT  - 23andMe
OT  - BioVu
OT  - EHR
OT  - EstBB
OT  - GWAS
OT  - HLA-B *55:01
OT  - PTPN22
OT  - UKBB
OT  - penicillin allergy
OT  - pharmacogenomics
COIS- 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.
FIR - Agee, Michelle
IR  - Agee M
FIR - Aslibekyan, Stella
IR  - Aslibekyan S
FIR - Bell, Robert K
IR  - Bell RK
FIR - Bryc, Katarzyna
IR  - Bryc K
FIR - Clark, Sarah K
IR  - Clark SK
FIR - Elson, Sarah L
IR  - Elson SL
FIR - Fletez-Brant, Kipper
IR  - Fletez-Brant K
FIR - Fontanillas, Pierre
IR  - Fontanillas P
FIR - Furlotte, Nicholas A
IR  - Furlotte NA
FIR - Gandhi, Pooja M
IR  - Gandhi PM
FIR - Heilbron, Karl
IR  - Heilbron K
FIR - Hicks, Barry
IR  - Hicks B
FIR - Hinds, David A
IR  - Hinds DA
FIR - Huber, Karen E
IR  - Huber KE
FIR - Jewett, Ethan M
IR  - Jewett EM
FIR - Jiang, Yunxuan
IR  - Jiang Y
FIR - Kleinman, Aaron
IR  - Kleinman A
FIR - Lin, Keng-Han
IR  - Lin KH
FIR - Litterman, Nadia K
IR  - Litterman NK
FIR - Luff, Marie K
IR  - Luff MK
FIR - McCreight, Jennifer C
IR  - McCreight JC
FIR - McIntyre, Matthew H
IR  - McIntyre MH
FIR - McManus, Kimberly F
IR  - McManus KF
FIR - Mountain, Joanna L
IR  - Mountain JL
FIR - Mozaffari, Sahar V
IR  - Mozaffari SV
FIR - Nandakumar, Priyanka
IR  - Nandakumar P
FIR - Noblin, Elizabeth S
IR  - Noblin ES
FIR - Northover, Carrie A M
IR  - Northover CAM
FIR - O'Connell, Jared
IR  - O'Connell J
FIR - Petrakovitz, Aaron A
IR  - Petrakovitz AA
FIR - Pitts, Steven J
IR  - Pitts SJ
FIR - Poznik, G David
IR  - Poznik GD
FIR - Sathirapongsasuti, J Fah
IR  - Sathirapongsasuti JF
FIR - Shastri, Anjali J
IR  - Shastri AJ
FIR - Shelton, Janie F
IR  - Shelton JF
FIR - Shringarpure, Suyash
IR  - Shringarpure S
FIR - Tian, Chao
IR  - Tian C
FIR - Tung, Joyce Y
IR  - Tung JY
FIR - Tunney, Robert J
IR  - Tunney RJ
FIR - Vacic, Vladimir
IR  - Vacic V
FIR - Wang, Xin
IR  - Wang X
FIR - Zare, Amir S
IR  - Zare AS
EDAT- 2020/09/06 06:00
MHDA- 2020/12/01 06:00
PMCR- 2021/04/01
CRDT- 2020/09/05 12:14
PHST- 2020/04/17 00:00 [received]
PHST- 2020/08/10 00:00 [accepted]
PHST- 2020/09/06 06:00 [pubmed]
PHST- 2020/12/01 06:00 [medline]
PHST- 2020/09/05 12:14 [entrez]
PHST- 2021/04/01 00:00 [pmc-release]
AID - S0002-9297(20)30276-7 [pii]
AID - 10.1016/j.ajhg.2020.08.008 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2020 Oct 1;107(4):612-621. doi: 10.1016/j.ajhg.2020.08.008. Epub 
      2020 Sep 3.