HLA Pharmacogenetic Markers of Drug Hypersensitivity in a Thai Population

Abstract

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.

High-Resolution HLA Typing of HLA-A, -B, -C, -DRB1, and -DQB1 in Kinh Vietnamese by Using Next-Generation Sequencing

“…The most frequent HLA-A alleles found in this study were A * 11:01:01 and A * 24:02:01. The high frequency of HLA-A * 11:01 and A * 24:02:01 is consistent with previous typing results of northern Kinh Vietnamese and other Asian populations, such as the Chinese, Thai, Indonesian, Korean, and Japanese (Lee et al, 2005;Hoa et al, 2008;Yuliwulandari et al, 2009;Shen et al, 2014;Ikeda et al, 2015;Nakkam et al, 2018). Among HLA-C alleles identified in this study, C * 07:02:01 was found to be widely distributed globally, while C * 01:02:01 was common in Asians (Lee et al, 2005;Shen et al, 2014;Ikeda et al, 2015;Nakkam et al, 2018).…”

“…Among HLA-C alleles identified in this study, C * 07:02:01 was found to be widely distributed globally, while C * 01:02:01 was common in Asians (Lee et al, 2005;Shen et al, 2014;Ikeda et al, 2015;Nakkam et al, 2018). The predominance of HLA-B * 15 alleles is a major distinguishing characteristic of the Kinh population from the Thai and Chinese groups (Shen et al, 2014;Nakkam et al, 2018). However, this predominance is similar in the Indonesian population (Yuliwulandari et al, 2009).…”

“…At the HLA-DRB1 locus, the most frequent allele was HLA-DRB1 * 12:02:01 (22.28%), which is common among South-East Asian populations (Busson et al, 2002;Hoa et al, 2008;Yuliwulandari et al, 2009;Nakkam et al, 2018) but infrequent among Northern East Asian groups, including Japanese and Koreans (Lee et al, 2005;Ikeda et al, 2015). Another similarity observed between the Kinh Vietnamese, Muong Vietnamese, and other South-East Asians is the predominance of HLA-DRB1 * 15:02:01 over HLA-DRB1 * 15:01:01, in contrast to what was observed among Northern East Asian populations.…”

“…Previously, HLA typing of Asian populations were mainly based on SSO-PCR (Lee et al, 2005;Yuliwulandari et al, 2009;Shen et al, 2014;Ikeda et al, 2015;Nakkam et al, 2018). Due to the finite amounts of probes designed to recognize the polymorphisms in the core exons, this technique only allows certain allele typing with 2-field resolution.…”

Recent developments and highlights in drug hypersensitivity

“…New genetic associations in DHRs have been found (Table ): HLA‐B*13:01‐restricted CD8 + T‐cell responses to dapsone and nitroso dapsone in Thai and Han Chinese populations ; this allele together with HLA‐B*56:02/04, CYP2C19*3 and omeprazole co‐medication, in phenytoin‐induced DRESS ; CYP2C19*3 and having Chinese ancestry for SJS ; HLA‐A*24:02 in anticonvulsant‐induced SCARs in Han Chinese ; HLA‐A*32:01 in vancomycin‐induced DRESS in a European ancestry population ; HLA‐B*35:05 allele correlates nevirapine patch test results ; and HLA‐B*48:01 with IR and HLA‐C*04:06, HLA‐C*08:01 and HLA‐DRB1*04:06 with NIR on BL reactions in Thai children . Finally, an extensive study in Thai population has revealed the existence of high prevalence (HLA‐B*13:01 for dapsone; HLA‐B*15:02 for carbamazepine and oxcarbazepine; HLA‐B*58:01, HLA‐A*33:03 and HLA‐C*03:02 for allopurinol; HLA‐C*08:01, HLA‐C*14:02 and HLA‐DRB1*12:02 for co‐trimoxazole) and low prevalence (HLA‐B*57:01 for abacavir, and HLA‐B*56:02/HLA‐B*56:04 for phenytoin) of pharmacogenetic markers of drug‐induced SCARs . These differences mark the cost‐effectiveness of the screening of these markers to prevent SCARs prior to prescription of some drugs in specific populations.…”