Genetic association of beta-lactams-induced hypersensitivity reactions: A systematic review of genome-wide evidence and meta-analysis of candidate genes

Lalita Lumkul; Pakpoom Wongyikul; Prapasri Kulalert; Mongkhon Sompornrattanaphan; Mongkol Lao-Araya; Mati Chuamanochan; Surapon Nochaiwong; Phichayut Phinyo

doi:10.1016/j.waojou.2023.100816

Genetic association of beta-lactams-induced hypersensitivity reactions: A systematic review of genome-wide evidence and meta-analysis of candidate genes

World Allergy Organ J. 2023 Sep 22;16(9):100816. doi: 10.1016/j.waojou.2023.100816. eCollection 2023 Sep.

Authors

Lalita Lumkul^{1

2}, Pakpoom Wongyikul¹, Prapasri Kulalert^{3

4}, Mongkhon Sompornrattanaphan⁵, Mongkol Lao-Araya⁶, Mati Chuamanochan^{7

8}, Surapon Nochaiwong^{7

9}, Phichayut Phinyo^{1

10

11}

Affiliations

¹ Center for Clinical Epidemiology and Clinical Statistics, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
² Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
³ Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University, Pathum Thani, 12120, Thailand.
⁴ Division of Allergy and Immunology, Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathum Thani, 12120, Thailand.
⁵ Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
⁶ Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
⁷ Pharmacoepidemiology and Statistics Research Center (PESRC), Chiang Mai University, Chiang Mai, 50200, Thailand.
⁸ Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
⁹ Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand.
¹⁰ Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
¹¹ Musculoskeletal Science and Translational Research (MSTR), Chiang Mai University, Chiang Mai 50200, Thailand.

Abstract

Importance: Beta-lactams (BLs) are the most prescribed antibiotics, being the most frequent cause of drug allergy. However, the association between BL allergy and genetic variations is still unclear.

Objective: This systematic review and meta-analysis aimed to summarize the genetic effects of BL-induced hypersensitivity using existing evidence.

Methods: We searched PubMed, Medline, Scopus, EMBASE, CINAHL, and Cochrane Library from inception to September 15, 2022 with no language restriction. Genetic association studies investigating genetic variant/polymorphism and risk of drug-induced hypersensitivity reactions among individuals receiving BL-antibiotics were included. We excluded studies of acute interstitial nephritis, drug-induced liver injury, serum sickness, and isolated drug fever. Data were comprehensively synthesized and quality of study were assessed using STrengthening the Reporting of Genetic Association Studies (STREGA). The record screening, extraction and quality assessment were performed by two reviewers and discussions were made to resolve discrepancies. The effects of each variant were pooled and evaluated by modified Venice criteria.

Results: A total of 9276 records were identified, and 31 studies were eligible for inclusion. Twenty-seven were candidate-gene association studies (5416 cases and 5939 controls), while the others were next-generation sequencing (NGS) or genome-wide association studies (GWASs) (119 838 cases and 1 487 111 controls). Forty-nine polymorphisms were identified and most of them located in allergic reaction pathways. Meta-analyses of 15 candidate variants in a mixture of both immediate and non-immediate reactions revealed weak genetic effects of rs1801275 (8 studies; n = 1,560; odd ratio 0.73; 95%CI: 0.57-0.93) and rs20541 (4 studies; n = 1,482; odd ratio 1.34; 95%CI: 1.07-1.68) in IL4R and IL13, respectively. Results from GWASs and NGS identified, and confirmed associations in HLA regions including HLA-DRA, HLA-B, HLA-DQA, HLA-DRB1, and HLA-DRB3.

Conclusion: Our study summarized genetic evidence influencing BL-induced hypersensitivity and estimated effects of potential variants. We postulated that the genomic studies provide better insights to the mechanism of reactions and suggest potential effects of HLA Class II variants. However, results were inconsistent and unable to generalize in different settings. Further high-throughput studies with a well-defined function, epigenetic interaction, incorporated with clinical factors, would be beneficial for risk identification in BL-induced hypersensitivity.

Keywords: Beta lactams hypersensitivity; Genetic polymorphism; Genome-wide association study; Meta-analysis; Systematic review.