HLA-B (*) 58:01 for Allopurinol-Induced Cutaneous Adverse Drug Reactions: Implication for Clinical Interpretation in Thailand.
HLA-B (*) 58:01 for Allopurinol-Induced Cutaneous Adverse Drug Reactions: Implication for Clinical Interpretation in Thailand.
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DOI：
10.3389/fphar.2016.00186
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发表时间：
2016
影响因子：
5.6
通讯作者：
Rerkpattanapipat T
中科院分区：
文献类型：
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作者：
Sukasem C;Jantararoungtong T;Kuntawong P;Puangpetch A;Koomdee N;Satapornpong P;Supapsophon P;Klaewsongkram J;Rerkpattanapipat T
背景：本研究的目的是探讨泰国人群中不同类型别嘌呤醇诱导的皮肤药物不良反应（CADR）的易感性，包括Stevens-Johnson综合征（SJS）、中毒性表皮坏死松解（TEN; SJS-TEN, n = 13）、嗜酸性粒细胞增多和全身症状的药物反应（DRESS, n = 10）和黄斑疹（MPE, n = 7），这些不良反应由HLA-B*58:01引起。方法：本病例-对照关联研究比较了30例别嘌呤醇诱导的CADR患者、别嘌呤醇耐受对照患者（n = 100）和泰国普通人群（n = 1095）。采用两阶段序列特异性寡核苷酸探针系统对患者人白细胞抗原B型（HLA-B）等位基因进行分型。结果：在30例别嘌呤醇所致CADR患者中，29例（96.7%）患者HLA-B*58:01至少为杂合，而别嘌呤醇耐受患者中这一比例仅为4.0% （p < 0.001）。在该人群中，HLA-B*58:01与别嘌呤醇诱导的CADR相关的比值比（OR）为696.0 （95% CI: 74.8-6475.0）。HLA-B*58:01等位基因存在于所有别嘌呤醇诱导的sks - ten患者中（OR = 579.0, 95%CI: 29.5 ~ 11362.7, p < 0.001）和DRESS患者中（OR = 430.3, 95%CI: 22.6 ~ 8958.9, p < 0.001）。此外，别嘌呤醇诱导的MPE患者HLA-B*58:01的OR值非常显著（OR值144.0,95%CI: 13.9 ~ 1497.0, p < 0.001）。结论：在本研究中，我们证实了HLAB*58:01与别嘌呤醇诱导的泰国人群SJS-TEN之间的关联。此外，我们在该人群中发现了HLA-B*58:01与别嘌呤醇诱导的DRESS和MPE之间的关联。因此，HLA-B*58:01可作为别嘌呤醇诱导CADR的药物遗传学标记物，包括SJS-TEN、DRESS和MPE。这些结果表明，在接受别嘌呤醇治疗的患者中筛查HLA-B*58:01等位基因将有助于预防泰国患者发生CARD的风险。无论表型如何，这是泰国血统患者中别嘌呤醇诱导的CADR的首次药物遗传学研究。在这项研究中，我们证实了HLA-B*58:01与泰国人群别嘌呤醇诱导的SJS-TEN、DRESS和MPE之间的关联。根据我们的研究结果，药理学解释可以推广到药物过敏，包括DRESS， SJS-TEN和MPE。总结
Background: The aim of this study was to investigate the predisposition to different types of allopurinol-induced cutaneous adverse drug reactions (CADR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN; SJS-TEN, n = 13), drug reaction with eosinophilia and systemic symptoms (DRESS, n = 10) and Maculopapular eruption (MPE; n = 7), conferred by HLA-B*58:01 in a Thai population. Methods: This case-control association study compares 30 patients with allopurinol-induced CADR, allopurinol-tolerant control patients (n = 100), and a Thai general population (n = 1095). Patients' human leukocyte antigen type B (HLA-B) alleles were genotyped by using a two-stage sequence-specific oligonucleotide probe system. Results: Of a total 30 patients with CADR due to allopurinol, 29 (96.7%) patients were found to be at least heterozygous for HLA-B*58:01, compared to only 4.0% in allopurinol-tolerant patients (p < 0.001). Odds ratio (OR) for the association of HLA-B*58:01 with allopurinol-induced CADR in this population was 696.0 (95% CI: 74.8–6475.0). The HLA-B*58:01 allele was present in all patients with allopurinol-induced SJS-TEN (OR = 579.0, 95%CI: 29.5–11362.7, p < 0.001) and DRESS (OR 430.3, 95%CI: 22.6–8958.9, p < 0.001). Additionally, OR of HLA-B*58:01 was highly significant in the allopurinol-induced MPE patients (OR 144.0, 95%CI: 13.9–1497.0, p < 0.001). Conclusion: In this study we confirmed the association between HLAB*58:01 and allopurinol-induced SJS-TEN in a Thai population. In addition, we identified an association between HLA-B*58:01 and allopurinol-induced DRESS and MPE in this population. Therefore, HLA-B*58:01 can be used as a pharmacogenetic marker for allopurinol-induced CADR including SJS-TEN, DRESS and MPE. These results suggest that screening for HLA-B*58:01 alleles in patients who will be treated with allopurinol would be clinically helpful in preventing the risk of developing CARD in a Thai patients. Regardless of phenotype, this is the first pharmacogenetic study of allopurinol-induced CADR in patients of Thai ancestry. In this study we confirmed the association between HLA-B*58:01 and allopurinol-induced SJS-TEN, DRESS, and MPE in Thai population. Regarding to our findings, the pharmacogenetic interpretation could be generalized to drug hypersensitivity including DRESS, SJS-TEN, and MPE. Summary