HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol
HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol
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DOI：
10.1073/pnas.0409500102
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发表时间：
2005-03-15
影响因子：
11.1
通讯作者：
Chen, YT
中科院分区：
文献类型：
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作者：
Hung, SL;Chung, WH;Chen, YT
别嘌醇是治疗痛风和高尿酸血症的常用药物，是引起严重皮肤不良反应(SCAR)的常见原因，包括药物超敏综合征、史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症。不良事件是不可预测的，并会导致严重的发病率和死亡率。为了确定别嘌醇-疤痕的遗传标记，我们进行了一项病例对照关联研究。我们招募了51名别嘌醇瘢痕患者和228名对照组(135名别嘌醇耐受者和93名普通人群中的健康人)，并对药物代谢和免疫反应相关基因的823个SNPs进行了基因分型。最初的筛查显示，别嘌醇-SCAR与MHC区域的SNP有很强的相关性，包括BAT3(编码人类白细胞抗原B相关转录本3)、MSH5(MutS同源5)和MICB(MIHC I类多肽相关序列B)(P<；10(-7))。然后我们确定了人类白细胞抗原A、B、C和DRB1等位基因。HLAB5801等位基因在51例别嘌醇瘢痕患者中全部(100%)存在，但在135例耐受患者中仅20例(15%)存在[优势比580.3(95%可信区间，34.4~9780.9)；校正P值=4.7x10(-24)]和93例健康人中19例(20%)[393.51(23.23~6665.26)；校正P值=8.1x10(-18)]。等位基因A*3303、Cw*0302和DRB1*0301处于连锁不平衡状态，与人类白细胞抗原B*5801形成扩展单倍型。我们的结果表明，别嘌醇-疤痕与中国汉族人的遗传易感性有很强的相关性。特别是，人类白细胞抗原-B*5801等位基因是这种危及生命的疾病的重要遗传危险因素。
Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MIHC class I polypeptide-related sequence B) (P < 10(-7)). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value = 4.7 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 10(-18)]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.