Genetic variants associated with T cell–mediated cutaneous adverse drug reactions: A PRISMA‐compliant systematic review—An EAACI position paper

Abstract

Abderrahim Oussalah and Vincent Yip First authors share an equal contribution.Jean-Louis Guéant and Munir Pirmohamed Senior authors share an equal contribution. AbstractDrug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMAcompliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future. K E Y W O R D Scutaneous adverse drug reactions, genetic variants, human leukocyte antigen genes, systematic review, T cell-mediated drug hypersensitivity reactions | 1071 OUSSALAH et AL. | MATERIAL S AND ME THODS | Electronic search queryThe literature search was conducted using MEDLINE ® -indexed literature using the PubMed search engine from the National Center for Biotechnology Information (www.pubmed.gov) (January 1966 to April 2019), Embase ® , and ISI Web of Knowledge using the full electronic search strategies detailed in the Appendix S1. Additional articles were retrieved from primary search references. The present systematic review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. 12 | Eligibility criteriaA study was considered eligible for the systematic review if it had investigated the association between any genetic variant and any T cell-mediated hypersensitivity reaction to drugs affecting the skin.Both candidate gene and genome-wide association study (GWAS) approaches were eligible for the systematic review. The exclusion criteria were as follows: non-English-language publication; meeting abstracts; case reports; review papers; comparison or assessment of genotyping methods; experimental mechanistic studies; no genetic association study between any genetic variant and any T cell-media...

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

“…Single HLA associations up until 2019 have been extensively reviewed (White et al, 2015;Karnes et al, 2019;Oussalah et al, 2020). Since then, further advancement in sequencing platforms has been providing increased resolution that has enabled discovery of novel HLA associations (LaHaye et al, 2016;van der Ven et al, 2018;Giannopoulou et al, 2019;Mimori et al, 2019 (Zhao et al, 2020).…”

Advances and novel developments in drug hypersensitivity diagnosis

“…A recent EAACI position paper performed an exhaustive revision about advances on the role of genetic susceptibility in DHRs. Genetic variations in HLA associated with susceptibility to hypersensitivity reactions for some drugs highlight the need to confirm current knowledge and to identify new associations for more accurate diagnosis, treatment, and management 96 (Figure 3).…”

Next-Generation Sequencing and Genotype Association Studies Reveal the Association of HLA-DRB3*02:02 With Delayed Hypersensitivity to Penicillins

“…8,10 Despite a high prevalence of nonimmediate reactions to penicillins, little is known about the influence of genetic determinants, in contrast to the pharmacogenetic data published on immediate reactions. [11][12][13][14] An Italian case-control study by Romano et al 15 assessed the HLA-A2 and HLA-DRw52 alleles in 24 patients with MPE caused by delayed hypersensitivity to aminopenicillins compared to 522 subjects from the general population and found that they were significantly more prevalent among the former. However, it is noteworthy that no genome-wide association study (GWAS) or HLA genotyping with next-generation sequencing (NGS) has been performed to evaluate the contribution of the genetic determinants.…”