Association between HLA alleles and beta-lactam antibiotics-related severe cutaneous adverse reactions

Introduction: Beta-lactam antibiotics are one of the most common causes of antibiotics-related severe cutaneous adverse reactions (SCARs) including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reactions with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Recent evidence demonstrated that the human leukocyte antigen (HLA) polymorphisms play important roles in the development of drug-related SCARs. This study aimed to extensively characterize the associations between HLA genetic polymorphisms and several phenotypes of SCARs related to beta-lactam antibiotics.Methods: Thirty-one Thai patients with beta-lactam antibiotics-related SCARs were enrolled in the study. A total of 183 unrelated native Thai subjects without any evidence of drug allergy were recruited as the control group. Genotyping of HLA class I and class II alleles was performed.Results: Six HLA alleles including HLA-A*01:01, HLA-B*50:01, HLA-C*06:02, HLA-DRB1*15:01, HLA-DQA1*03:01, and HLA-DQB1*03:02, were significantly associated with beta-lactam antibiotics-related SCARs. The highest risk of SCARs was observed in patients with the HLA-B*50:01 allele (OR = 12.6, 95% CI = 1.1–142.9, p = 0.042), followed by the HLA-DQB1*03:02 allele (OR = 5.8, 95% CI = 1.5–22.0, p = 0.012) and the HLA-C*06:02 allele (OR = 5.7, 95% CI = 1.6–19.9, p = 0.011). According to the phenotypes of SCARs related to beta-lactam antibiotics, the higher risk of SJS/TEN was observed in patients with HLA-A*03:02, HLA-B*46:02 (OR = 17.5, 95% CI = 1.5–201.6, p = 0.033), HLA-A*02:06, HLA-B*57:01 (OR = 9.5, 95% CI = 1.3–71.5, p = 0.028), HLA-DQB1*03:02 (OR = 7.5, 95% CI = 1.8–30.9, p = 0.008), or HLA-C*06:02 (OR = 4.9, 95% CI = 1.1–21.4, p = 0.008). While eight HLA alleles including HLA-A*02:05, HLA-A*02:11, HLA-B*37:01, HLA-B*38:01, HLA-B*50:01, HLA-C*06:02, HLA-C*03:09, and HLA-DRB1*15:01 were associated with AGEP, the highest risk of AGEP was observed in patients with the HLA-B*50:01 allele (OR = 60.7, 95% CI = 4.8–765.00, p = 0.005). Among the four HLA alleles associated with DRESS including HLA-C*04:06, HLA-DRB1*04:05, HLA-DRB1*11:01, and HLA-DQB1*04:01, the HLA-C*04:06 allele had the highest risk of beta-lactam antibiotics-related DRESS (OR = 60.0, 95% CI = 3.0–1202.1, p = 0.043). However, these associations did not achieve statistical significance after Bonferroni’s correction. Apart from the HLA risk alleles, the HLA-A*02:07 allele appeared to be a protective factor against beta-lactam antibiotic-related SCARs (OR = 0.1, 95% CI = 0.0–0.5, p = 3.7 × 10−4, Pc = 0.012).Conclusion: This study demonstrated the candidate HLA alleles that are significantly associated with several phenotypes of beta-lactam antibiotics-related SCARs. However, whether the HLA alleles observed in this study can be used as valid genetic markers for SCARs related to beta-lactam antibiotics needs to be further explored in other ethnicities and larger cohort studies

Genetic Association of Co‐Trimoxazole‐Induced Severe Cutaneous Adverse Reactions Is Phenotype‐Specific: HLA Class I Genotypes and Haplotypes

Co‐trimoxazole (CTX) causes various forms of severe cutaneous adverse reactions (SCARs). This case‐control study was conducted to investigate the involvement between genetic variants of human leukocyte antigen (HLA) and CYP2C9 in CTX‐induced SCARs, including Stevens‐Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in Thai patients. Thirty cases of CTX‐induced SCARs were enrolled and compared with 91 CTX‐tolerant controls and 150 people from the general Thai population. Cases comprised 18 SJS/TEN and 12 DRESS patients. This study demonstrated that genetic association of CTX‐induced SCARs was phenotype‐specific. HLA‐B*15:02 and HLA‐C*08:01 alleles were significantly associated with CTX‐induced SJS/TEN, whereas the HLA‐B*13:01 allele was significantly associated with CTX‐induced DRESS. In addition, a significant higher frequency of HLA‐A*11:01‐B*15:02 and HLA‐B*13:01‐C*03:04 haplotypes were detected in the group of CTX‐induced Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS cases, respectively. Genetic association of CTX‐induced SCARs is phenotype‐specific. Interestingly, these association was observed only in HIV‐infected patients but not in non‐HIV‐infected patients

HLA Pharmacogenetic Markers of Drug Hypersensitivity in a Thai Population

Severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) are potentially life-threatening cutaneous reactions caused by several drugs. Recently, a number of genes encoding for human antigen presenting proteins, HLA alleles, have been discovered as valid pharmacogenetic markers for prediction of these life-threatening reactions. This study was aimed to determine the distribution of HLA alleles including the HLA class I and class II genes in 183 unrelated individuals of a Thai population using high resolution HLA genotyping in order to obtain 2-field data (4-digit resolution) and compare the frequencies of the HLA alleles that have been proposed as markers of SCARs with other ethnics. Results revealed a high prevalence of pharmacogenetic markers of drug-induced SCARs e.g., B*13:01 for dapsone; B*15:02 for carbamazepine and oxcarbazepine; B*58:01, A*33:03 and C*03:02 for allopurinol; C*08:01, C*14:02 and DRB1*12:02 for co-trimoxazole. Whereas, low prevalence of pharmacogenetic markers of SCARs induced by abacavir, B*57:01 and phenytoin, B*56:02/B*56:04 were noticed. The allele frequencies of B*13:01, B*15:02, and B*58:01 observed in a Thai population were significantly higher than those reported in Japanese and Caucasian populations. Similar to those observed in other Southeast Asian populations, low frequencies of A*31:01 and B*57:01 alleles were noted in the study population. Based on the frequencies of HLA pharmacogenetic markers, Thai and other Southeast Asian populations may at higher risk of drug-induced SCARs compared with Caucasian population

Comparison between the HLA-B∗58 : 01 Allele and Single-Nucleotide Polymorphisms in Chromosome 6 for Prediction of Allopurinol-Induced Severe Cutaneous Adverse Reactions

Severe cutaneous adverse drug reactions (SCARs) are life-threatening reactions. The strong association between the HLA-B∗58 : 01 allele and allopurinol-induced SCARs is well recognized. Screening for HLA-B∗58 : 01 allele before prescribing allopurinol in some populations has been recommended. Several single-nucleotide polymorphisms (SNPs) in chromosome 6 have been found to be tightly linked with the HLA allele, and these SNPs have been proposed as surrogate markers of the HLA-B∗58 : 01 allele. This study aimed to evaluate the association between three SNPs in chromosome 6 and allopurinol-induced SCARs in a Thai population. The linkage disequilibrium between the HLA-B∗58 : 01 allele and these SNPs was also evaluated. Results showed that three SNPs including rs9263726, rs2734583, and rs3099844 were significantly associated with allopurinol-induced SCARs but with a lower degree of association when compared with the HLA-B∗58 : 01 allele. The sensitivity, specificity, PPV, and NPV of these SNPs were comparable to those of the HLA-B∗58 : 01 allele. Although detection of the SNP is simpler and less expensive compared with that of the HLA-B∗58 : 01 allele, these SNPs were not perfectly linked with the HLA-B∗58 : 01 allele. Screening using these SNPs as surrogate markers of the HLA-B∗58 : 01 allele to avoid SCARs prior to allopurinol administration needs caution because of their imperfect linkage with the HLA-B∗58 : 01 allele