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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DOI：
10.1093/hmg/ddq537
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Nakamura, Yusuke
中科院分区：
文献类型：
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作者：
Ozeki, Takeshi;Mushiroda, Taisei;Nakamura, Yusuke
已知抗惊厥药卡马西平（CBZ）会出现皮肤药物不良反应（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）和药物诱导的超敏反应综合征（DIHS）。为了确定对CBZ诱导的cADR易感的基因，我们在日本53例CBZ诱导的cADR受试者（包括SJS、TEN和DIHS）和882例一般人群受试者中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，12个SNP与CBZ诱导的cADR显著相关，rs 1633021与CBZ诱导的cADR相关性的P值最小（P = 1.18 x 10（-13））。这些SNPs位于染色体6p21.33上的430 kb连锁不平衡块内，包括HLA-A位点。因此，我们对61例病例和376例CBZ给药未显示cADR的患者进行了HLA-A等位基因分型结果发现，60.7%（37/61）的CBZ诱导的cADR患者存在HLA-A*3101，但仅12.5%（47/376）的CBZ耐受对照中存在HLA-A*3101（比值比= 10.8，95%可信区间5.9-19.6，P = 3.64 x 10（-15）），这意味着当我们应用HLA-A*3101作为CBZ诱导的cADR的风险预测因子时，该等位基因具有60.7%的敏感性和87.5%的特异性。尽管DIHS在临床上与SJS和TEN不同，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。本研究结果可为抗惊厥药物个体化用药提供参考。
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 x 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-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 = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 x 10(-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.