The Association Between HLA-B Variants and Amoxicillin-induced Severe Cutaneous Adverse Reactions in Chinese Han Population

Overview

Journal Front Pharmacol

Date 2024 Jun 12

PMID 38863977

Authors

Ting Wang

Jin Yang

Fanping Yang

Ye Cheng

Zichong Huang

Bei Li

Linlin Yang

Qinghe Xing

Xiaoqun Luo

Affiliations

Soon will be listed here.

Abstract

Background: Amoxicillin (AMX) is among the most prescribed and the best tolerated antimicrobials worldwide. However, it can occasionally trigger severe cutaneous adverse reactions (SCAR) with a significant morbidity and mortality. The genetic factors that may be relevant to AMX-induced SCAR (AMX-SCAR) remain unclear. Identification of the genetic risk factor may prevent patients from the risk of AMX exposure and resume therapy with other falsely implicated drugs.

Methodology: Four patients with AMX-SCAR, 1,000 population control and 100 AMX-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between AMX and risk HLA proteins.

Results: Compared with AMX-tolerant controls, a significant association of with AMX-SCAR was validated [odds ratio (OR) = 22.9, 95% confidence interval (CI): 1.68-1275.67; = 7.34 × 10]. Moreover, 75% carriers of in four patients with AMX-SCAR, and the carrier frequency of 10.7% in 1,000 control individuals and 11.0% in 100 AMX-tolerant controls, respectively. Within HLA-B protein, the S140 present in all cases and demonstrated the strongest association with AMX-SCAR [OR = 53.5, = 5.18 × 10]. Molecular docking results also confirmed the interaction between AMX and S140 of the HLA-B protein, thus eliminating the false-positive results during in association analysis.

Conclusion: Our findings suggest that genetic susceptibility may be involved in the development of AMX-SCAR in Han Chinese. However, whether the HLA-B variants observed in this study can be used as an effective genetic marker of AMX-induced SCAR still needs to be further explored in larger cohort studies and other ethnic populations.

References

Raychaudhuri S, Sandor C, Stahl E, Freudenberg J, Lee H, Jia X . Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012; 44(3):291-6. PMC: 3288335. DOI: 10.1038/ng.1076. View

Sodhi K, Singh C, Kumar M, Singh D . Whole-genome sequencing of sp. strain MMA: insight into the antibiotic and heavy metal resistant genes. Front Pharmacol. 2023; 14:1144561. PMC: 10213877. DOI: 10.3389/fphar.2023.1144561. View

Chu X, Yang M, Song Z, Dong Y, Li C, Shen M . Fine mapping MHC associations in Graves' disease and its clinical subtypes in Han Chinese. J Med Genet. 2018; 55(10):685-692. PMC: 6161647. DOI: 10.1136/jmedgenet-2017-105146. View

Mallal S, Phillips E, Carosi G, Molina J, Workman C, Tomazic J . HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008; 358(6):568-79. DOI: 10.1056/NEJMoa0706135. View

Pejcic A, Milosavljevic M, Folic M, Fernandes D, Bentes J, Djesevic M . Amoxicillin-associated Stevens-Johnson syndrome or toxic epidermal necrolysis: systematic review. J Chemother. 2022; 35(2):75-86. DOI: 10.1080/1120009X.2022.2051128. View

Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L . The DRESS syndrome: a literature review. Am J Med. 2011; 124(7):588-97. DOI: 10.1016/j.amjmed.2011.01.017. View

Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau J . Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002; 138(8):1019-24. DOI: 10.1001/archderm.138.8.1019. View

Girelli F, Bernardi S, Gardelli L, Bassi B, Parente G, Dubini A . A New Case of DRESS Syndrome Induced by Sulfasalazine and Triggered by Amoxicillin. Case Rep Rheumatol. 2013; 2013:409152. PMC: 3723001. DOI: 10.1155/2013/409152. View

Barker D, Maccari G, Georgiou X, Cooper M, Flicek P, Robinson J . The IPD-IMGT/HLA Database. Nucleic Acids Res. 2022; 51(D1):D1053-D1060. PMC: 9825470. DOI: 10.1093/nar/gkac1011. View

10.

Chung W, Hung S, Hong H, Hsih M, Yang L, Ho H . Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004; 428(6982):486. DOI: 10.1038/428486a. View

11.

Illing P, Vivian J, Dudek N, Kostenko L, Chen Z, Bharadwaj M . Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature. 2012; 486(7404):554-8. DOI: 10.1038/nature11147. View

12.

Romano A, Oussalah A, Chery C, Gueant-Rodriguez R, Gaeta F, Cornejo-Garcia J . Next-generation sequencing and genotype association studies reveal the association of HLA-DRB3*02:02 with delayed hypersensitivity to penicillins. Allergy. 2021; 77(6):1827-1834. DOI: 10.1111/all.15147. View

13.

Wattanachai P, Amornpinyo W, Konyoung P, Purimart D, Khunarkornsiri U, Pattanacheewapull O . Association between alleles and beta-lactam antibiotics-related severe cutaneous adverse reactions. Front Pharmacol. 2023; 14:1248386. PMC: 10546186. DOI: 10.3389/fphar.2023.1248386. View

14.

Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K . ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther. 2010; 88(1):60-8. DOI: 10.1038/clpt.2009.252. View

15.

Zhang F, Liu H, Irwanto A, Fu X, Li Y, Yu G . HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med. 2013; 369(17):1620-8. DOI: 10.1056/NEJMoa1213096. View

16.

Jiang M, Yang F, Zhang L, Xu D, Jia Y, Cheng Y . Unique motif shared by HLA-B*59:01 and HLA-B*55:02 is associated with methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. J Eur Acad Dermatol Venereol. 2022; 36(6):873-880. DOI: 10.1111/jdv.17980. View

17.

Naranjo C, Busto U, Sellers E, Sandor P, Ruiz I, Roberts E . A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30(2):239-45. DOI: 10.1038/clpt.1981.154. View

18.

Hung S, Chung W, Liou L, Chu C, Lin M, Huang H . HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005; 102(11):4134-9. PMC: 554812. DOI: 10.1073/pnas.0409500102. View

19.

Um S, Lee S, Kim Y, Kim K, Son C, Roh M . Clinical features of drug-induced hypersensitivity syndrome in 38 patients. J Investig Allergol Clin Immunol. 2011; 20(7):556-62. View

20.

Wei C, Chung W, Huang H, Chen Y, Hung S . Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2012; 129(6):1562-9.e5. DOI: 10.1016/j.jaci.2011.12.990. View