PT  - JOURNAL ARTICLE
AU  - Kristi Krebs
AU  - Jonas Bovijn
AU  - Maarja Lepamets
AU  - Jenny C Censin
AU  - Tuuli Jürgenson
AU  - Dage Särg
AU  - Yang Luo
AU  - Line Skotte
AU  - Frank Geller
AU  - Bjarke Feenstra
AU  - Wei Wang
AU  - Adam Auton
AU  - 23andMe Research Team
AU  - Soumya Raychaudhuri
AU  - Tõnu Esko
AU  - Andres Metspalu
AU  - Sven Laur
AU  - Michael V Holmes
AU  - Cecilia M Lindgren
AU  - Reedik Mägi
AU  - Lili Milani
AU  - João Fadista
TI  - Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy
AID  - 10.1101/2020.02.27.967497
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.27.967497
4099  - http://biorxiv.org/content/early/2020/03/02/2020.02.27.967497.short
4100  - http://biorxiv.org/content/early/2020/03/02/2020.02.27.967497.full
AB  - 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.