Research Group for Pharmacogenomics, RIKEN Center for Genomic Medicine, Yokohama 230-0045, Japan.
Hum Mol Genet. 2011 Mar 1;20(5):1034-41. doi: 10.1093/hmg/ddq537. Epub 2010 Dec 10.
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 = 1.18 × 10⁻¹³). 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-A3101 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 = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 × 10⁻¹⁵), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A3101 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.
一种抗惊厥药卡马西平（CBZ）已知会引起皮肤不良反应（cADR），包括史蒂文斯-约翰逊综合征（SJS）、中毒性表皮坏死松解症（TEN）和药物引起的超敏反应综合征（DIHS）。为了确定易受 CBZ 诱导的 cADR 影响的基因（s），我们对 53 名 CBZ 诱导的 cADR 患者（包括 SJS、TEN 和 DIHS）和日本 882 名普通人群进行了全基因组关联研究（GWAS）。在 GWAS 分析的单核苷酸多态性（SNP）中，有 12 个 SNP 与 CBZ 诱导的 cADR 显著相关，rs1633021 与 CBZ 诱导的 cADR 相关性的 P 值最小（P=1.18×10⁻¹³）。这些 SNP 位于 6p21.33 染色体上一个 430 kb 的连锁不平衡块内，包括 HLA-A 基因座。因此，我们对 61 例 CBZ 诱导的 cADR 患者（CBZ 诱导的 cADR 患者）和 376 例 CBZ 耐受对照患者（CBZ 耐受对照）的个体 HLA-A 等位基因进行了基因分型，发现 HLA-A3101 存在于 60.7%（37/61）的 CBZ 诱导的 cADR 患者中，但仅存在于 12.5%（47/376）的 CBZ 耐受对照中（比值比=10.8，95%置信区间 5.9-19.6，P=3.64×10⁻¹⁵），这意味着当我们将 HLA-A3101 作为 CBZ 诱导的 cADR 的风险预测因子时，该等位基因的敏感性为 60.7%，特异性为 87.5%。虽然 DIHS 在临床上与 SJS 和 TEN 不同，但我们这里提供的数据表明，它们具有共同的遗传因素和共同的病理生理机制。我们的发现应该为抗惊厥药物个体化治疗的决策提供有用的信息。
