ABSTRACT
Drug reactions (DR) are grouped into two basic classes. Allergic reactions through by immunological mechanisms is one of them; the second is the drug hypersensitivity reactions (DHR) that occur without the engagment of a specific immunological response. Prevelance of DHR is a extensive cause of morbidity and mortality. These severe reactions are originated from specific human leukocyte antigen (HLA) alleles. Since, HLA genes include the high rate of polymorphic loci in the genome significantly. Thus, genetic predisposition rather than the pharmacological dose effect in the etiology of DHR account for one of the most intriguing sites of pharmacogenetic research. Specific HLA associations with DHR may be varry between geographic regions and ethnic groups. Even among individuals of the same population, drug response and sensitivity may differ according as HLA alleles. Numerous investigations have provided evidence that some of HLA’s increase the risk of growing DHR. In view of the fact that the interconnection between HLA, drugs and T cell receptors in drug-responsive T cell reaction may vary widely depending on HLA alleles. According to, the allele type, the activation of the T cell and its interaction with the antigen is the most significant molecular system that causes variations in the immune response. While these features reveal the didtinctive genetic relationship of HLA alleles through DHR, there may be individuals who metabolize the drug rapidly or develop a toxic response without metabolizing it at according to HLA allele types within the pharmacokinetic effect. In this line, determining pharmacogenomic datas in societies, discovering new evidence for HLA alleles and drug sensitivity, and verifying the findings with the evidence rate will provide great benefits both in terms of health quality for drug use and cost effectiveness. Personalized pharmacological treatment with HLA identification before drug use is one of the current treatment targets in developing countries. In this review, the models that cause drug hypersensitivity reactions, the most frequently reacting drugs, the associated HLA alleles and the clinical presentations were investigated. Keywords: HLA, drug, hypersensitivity reactions
Cite this Article As :
Somuncu MN, Zamani AG. HLA-Related Drug Hypsensitivity Reactions. Selcuk Med J 2024;40(2): 88-93
1. Robinson J, Halliwell JA, Hayhurst JD, et al. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res 2015; 43: 423-431.
2. Reche PA, Reinherz EL. Sequence variability analysis of human class I and class II MHC molecules: functional and structural correlates of amino acid polymorphisms. J Mol Biol 2003;331(3):623-641.
3. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139(8):683-693.
4. Pichler W, Yawalkar N, Schmid S, et al. Pathogenesis of drug-induced exanthems. Allergy 2002;57(10):884-893.
5. Jaruthamsophon K, Thomson PJ, Sukasem C, et al. HLA Allele-Restricted Immune-Mediated Adverse Drug Reactions: Framework for Genetic Prediction. Annu Rev Pharmacol Toxicol 2022;62:509-529.
6. Britschgi M, von Greyerz S, Burkhart C, et al. Molecular aspects of drug recognition by specific T cells. Curr. Drug Targets 2003; 4:1–11 8.
7. Pompeu YA, Stewart JD, Mallal S, et al. The structural basis of HLA associated drug hypersensitivity syndromes. Immunol. Rev. 2012; 250:158–66.
8. Shanbhag SS, Koduri MA, Kannabiran C, et al. Genetic Markers for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in the Asian Indian Population: Implications on Prevention. Front Genet 2021; 12;11:607532.
9. Stirton H, Shear NH, Dodiuk-Gad RP. Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS)/Drug-Induced Hypersensitivity Syndrome (DiHS)-Readdressing the DReSS. Biomedicines 2022; 26;10(5):999.
11. Garbe E. Non-chemotherapy drug-induced agranulocytosis. Expert Opin Drug Saf 2007; 6(3):323-35.
12. Whirl-Carrillo M, McDonagh EM, Hebert JM et al. Pharmacogenomics knowledge for personalized medicine. Clin. Pharmacol 2012; 92(4); 414–417.
13. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359(9312):1121–1122.
14. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358(6):568–579.
15. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359(9308):727–732.
16. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 2008;46(7):1111-1118.
17. Çelik G, Dursun B. 16. Türkiye Ulusal Allerji ve Klinik İmmünoloji Derneği. (eds). İlaç aşırı duyarlılık reaksiyonlarına yaklaşım ulusal rehber güncellemesi. Buluş Tasarım, Ankara, 2019.
18. Masmoudi HC, Afify N, Alnaqbi H, et al. HLA pharmacogenetic markers of drug hypersensitivity from the perspective of the populations of the Greater Middle East. Pharmacogenomics 2022;23(12):695-708.
19. White KD, Chung WH, Hung SI, Mallal S, Phillips EJ. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 2015;136(2):219-34.
20. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428(6982):486.
21. Mehta TY, Prajapati LM, Mittal B, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol 2009;75(6):579-582.
22. Kaniwa N, Saito Y, Aihara M, et al. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia 2010;51(12):2461–2465.
23. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364(12):1134-1143.
24. Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenet. Genomics 2014; 24(2), 94–112.
25. Ksouda K, Affes H, Mahfoudh N et al. HLA-A*31:01 and carbamazepine-induced DRESS syndrom in a sample of North African population. Seizure 2017; 53, 42–46.
26. Li LJ, Hu FY, Wu XT, An DM, Yan B, Zhou D. Predictive markers for carbamazepine and lamotrigine-induced maculopapular exanthema in Han Chinese. Epilepsy Res 2013;106(1-2), 296–300.
27. Man CB, Kwan P, Baum L, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 2007;48(5):1015–1018.
28. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005; 15;102(11):4134-9.
29. Cristallo AF, Schroeder J, Citterio A et al. A study of HLA class I and class II 4-digit allele level in Stevens–Johnson syndrome and toxic epidermal necrolysis. Int. J. Immunogenet. 2011; 38(4), 303–309
30. Cornejo Castro EM, Carr DF, et al. HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: a systematic review of the literature and meta-analysis. Pharmacogenet Genomics 2015; 25(4), 186–198.
31. Dekker JW, Nizankowska E, Schmitz-Schumann M, et al. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin. Exp. Allergy 1997; 27(5), 574–577.
32. Tangamornsuksan W, Kongkaew C, Scholfield CN, Subongkot S, Lohitnavy M. HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity: a systematic review and meta-analysis. Pharmacogenomics J. 2020; 20(1):47-56.
33. Choi JH, Lee KW, Oh HB et al. HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J. Allergy Clin. Immunol 2004;113(3), 562–564.
34. Fan WL, Shiao MS, Hui RC, et al. HLA Association with Drug-Induced Adverse Reactions. J Immunol Res 2017:3186328.
35. Bunce M, Passey B. HLA typing by sequence-specific primers. Methods Mol Biol. 2013;1034:147-159.
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Keywords
DHR, HLA
