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Penicillin Allergy Linked to HLA-B Allele in Genome-Wide Association Study

NEW YORK – Using biobank and electronic health record data, an international team of researchers has tied an HLA allele to being allergic to penicillin. 


Adverse drug reactions are common and lead to about 100,000 deaths a year in the US. Antibiotics, particularly those from the beta-lactam class like penicillin, are a frequent cause of adverse drug reactions. Penicillin allergies can lead to reactions ranging from a rash to life-threatening systemic effects.

Researchers led by João Fadista from the Statens Serum Institut in Copenhagen extracted data on penicillin allergies from three biobanks of electronic health records to conduct a genome-wide association study. As they reported in the American Journal of Human Genetics on Thursday, their analysis implicated a human leukocyte antigen (HLA) allele in being allergic to penicillin, a finding they confirmed in a fourth dataset. 


"We have leveraged data from four large-scale cohorts, including more than 100,000 cases, to provide insights into the genetic architecture associated with self-reported penicillin allergy, and provide robust evidence implicating the HLA-B*55:01 allele and autoimmune factors in this condition," co-lead author Lili Milani from the University of Tartu said in a statement. 


The researchers conducted a genome-wide association study using more than 600,000 individuals of European ancestry from the UK Biobank, Estonian Biobank and Vanderbilt University's BioVu biobank to search for variants linked to penicillin allergy. Based on diagnostic codes and other electronic health record data, the researchers identified more than 29,000 people within these three cohorts who reported a penicillin allergy. 


A meta-analysis of GWAS conducted in the three cohorts uncovered two genome-wide loci linked to penicillin allergy: a signal in the major histocompatibility complex (MHC) and one in the PTPN22 gene. Imputation and other analyses further homed in on the HLA-B*55:01 allele within the MHC as being linked to penicillin allergy. The HLA region of the genome, the researchers noted, is highly polymorphic and involved in adaptive immune response. It also has been implicated in hypersensitivity reactions like those observed among individuals who are allergic to penicillin. 


The other hit the researchers uncovered is in PTPN22, which encodes a tyrosine phosphatase that is involved in the regulation of immune cell signaling. It is also a risk factor for rheumatoid arthritis. 


The researchers additionally confirmed the association between the HLA-B*55:01 allele and penicillin allergy in a cohort of nearly 88,000 cases and 1 million controls of European ancestry from the 23andMe research cohort. They also noted that the SNP marking the HLA-B*55:01 allele is also linked to promoter and enhancer marks in T cells, suggesting a regulatory function. 


They further estimated that individuals with the HLA-B*55:01 allele had 33 percent higher relative odds of having a penicillin allergy. 


Using UKB PheWas data, the researchers also uncovered associations between the HLA-B*55:01 allele and clinical traits like lower white blood cell and lymphocyte counts. In addition, they uncovered a genetic correlation between penicillin allergy and rheumatoid arthritis as well as between it and psoriasis using the LDhub database.  


This "genome-wide genetic correlation analysis of the self-reported penicillin allergy results revealed overlap with the autoimmune diseases rheumatoid arthritis and psoriasis," Fadista said in a statement. "This, together with the finding in the PTPN22 gene, indicates a possible underlying autoimmune factor in the development of penicillin allergy investigated in our study."