Nordic Researchers Link Penicillin Allergy to Immune System Genes

By Carol Morton

1 February 2021. A variant in an immune system gene may play a role in penicillin allergy, one of the most common drug side effects, according to a study led by researchers in Denmark and Estonia.

The study, published in the American Journal of Human Genetics, showcases the promise of using electronic health records in combination with genetic information to understand the risk of adverse drug reactions.

The findings come from two teams of Nordic researchers who joined forces after discovering they both were exploring the genetic architecture of hypersensitivity to penicillin and the related antibiotics amoxicillin and ampicillin.

               Lili Milani

“It’s a funny story,” says Lili Milani, pharmacogenetics professor and head of the Estonian Personalized Medicine Initiative at the Estonian Genome Centre, University of Tartu. She got an email from João Fadista, then a senior researcher at the Statens Serum Institut in Denmark. Fadista and his colleagues had found a genetic signal for penicillin allergy and wanted to independently replicate it. Meanwhile, Kristi Krebs, a postdoctoral fellow in Milani’s lab, had come up with a similar preliminary finding in the same gene.

Together, the researchers and their co-authors leveraged data from four sources in three countries—Estonian Biobank, UK Biobank, Vanderbilt University Medical Center’s biobank (BioVU) and, for independent replication, 23andMe’s research cohort.

Image removed.
               João Fadista

In each of the four biobank cohorts, they identified penicillin allergies from self-reported data and electronic health records for a total of 100,000 cases of European ancestry.

In genome-wide association studies (GWAS) of each cohort, a strong signal emerged from the major histocompatibility complex (MHC) I gene HLA-B, which helps defend the body from foreign invaders by presenting antigens to T cells. The techniques of imputing and fine mapping helped researchers narrow the signal down to the HLA-B*55:01 allele.

“The variant may predispose to a T cell mediate process leading to a delayed penicillin reaction,” Krebs said in a press release.

The GWAS also detected a variant in the PTPN22 gene that has been associated with several autoimmune diseases and with drug-induced liver injury. Independent of the PTPN22 gene variant, the team found a genetic correlation between penicillin allergy and rheumatoid arthritis and psoriasis.

The overlap with the autoimmune diseases and the PTPN22 gene “indicates a possible underlying autoimmune factor in the development of penicillin allergy,” Fadista says in the press release. Fadista is now a principal scientist in bioinformatics and data mining at Novo Nordisk.

So far, genetic factors have only been found for rare severe allergic reactions to penicillin, the authors write in the paper. Most of the cases in this study appeared to be a less-severe form, with 5 percent or less reporting breathing difficulty or anaphylaxis in the Estonia and BioVU cohorts. The usual symptom is a delayed skin rash, and people often outgrow the reaction as adults.

The findings don’t have immediate clinical application, but they hint at the possibility of developing polygenic risk scores for adverse drug reactions in the future, and show how data in biobanks and electronic health records can contribute to developing prognostic markers and personalized treatment, Milani says.

The next step for Milani and her colleagues will be to increase the sample size and examine clinical cohorts to better understand the penicillin allergy and also to look at reactions to other medications. Her team also wants to identify more genetic variants that influence responses to drugs and understand the effects of those variants.

Drug allergies are rare, and collecting the data from electronic medical records is challenging, she says. Doctors rarely use the standardized international procedure code, such as the ICD10, and in the free text they may abbreviate, misspell, or use different languages to refer to a drug implicated in a reaction.

The collaborative effort includes scientists from the Estonian Genome Center, University of Tartu, Statens Serum Institut, University of Oxford, Vanderbilt University Medical Center, Harvard Medical School, Broad Institute of MIT and Harvard, and 23andMe.


Genome-wide Study Identifies Association between HLA-B55:01 and Self-Reported Penicillin Allergy.
Krebs K, Bovijn J, Zheng N, Lepamets M, Censin JC, Jürgenson T, Särg D, Abner E, Laisk T, Luo Y, Skotte L, Geller F, Feenstra B, Wang W, Auton A; 23andMe Research Team, Raychaudhuri S, Esko T, Metspalu A, Laur S, Roden DM, Wei WQ, Holmes MV, Lindgren CM, Phillips EJ, Mägi R, Milani L, Fadista J.
Am J Hum Genet. 2020 Oct 1;107(4):612-621.

Image credits: Renee Altrov/Courtesy: L.Milani; Courtesy: J.Fadista