Genome-wide association study identifies HLA-A ∗ 3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population
Genome-wide association study identifies HLA-A ∗ 3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population
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卡马西平(CBZ)是一种抗惊厥药物，其皮肤不良反应(CADR)的发生率包括Stevens-Johnson综合征(SJS)、中毒性表皮坏死松解症(TEN)和药物诱导的超敏综合征(DIHS)。为了确定卡马西平诱导的cADR易感基因(S)，我们对53例cADR患者进行了全基因组关联研究，其中包括SJS、TEN和DIHS，以及日本普通人群中的882人。在所分析的单核苷酸多态(SNP)中，12个SNP与卡马西平诱导的cADR显著相关，rs1633021与卡马西平诱导的cADR相关的P值最小(P5 1.18 3 10 2 13)。这些SNPs位于染色体6p21.33上一个430kb的连锁不平衡区块内，包括人类白细胞抗原A基因座。因此，我们对服用卡巴唑的61例患者和376例未出现cADR的患者进行了个体HLAA等位基因分型，发现60.7%(37/61)的患者存在HLAA∗3101，而耐受组只有12.5%(47/376)(优势比510.8，95%可信区间5.9-19.6，P53.64 3 10215)，提示该等位基因对fi-Acadrs3101的敏感性为60.7%，特异性为87.5%。∗3101是cADR的危险预测因子。虽然DHS在临床上不同于SJS和TEN，但我们的数据表明，它们具有共同的遗传因素和共同的病理生理机制。我们的fi结果将为制定抗惊厥药物个体化用药的决策提供有用的信息。
An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P -value for association with CBZ-induced cADRs ( P 5 1.18 3 10 2 13 ). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A ∗ 3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio 5 10.8, 95% confidence interval 5.9–19.6, P 5 3.64 3 10 2 15 ), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A ∗ 3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.