人类白细胞抗原基因与卡马西平等药物诱发皮肤型药物不良反应相关性在新疆维、汉民族患者间的差异性研究

Drugs such as carbamazepine oxcarbazepine and lamotrigine are used for the treatment of epilepsy ,there is drug cross reactions due to the similarity of the structure. Drugs of anti-epilepsy such as carbamazepine can induced severe skin reactiongs including SJS/TEN, the pathogenesis is not clear, but clinical findings that genetic factors is one of the possible reasons, and racial differences is also a possible cause. Study shows Taiwan Han people carrying HLA-B * 1502 gene strongly associated with Carbamazepine-induced SJS / TEN and other skin reactions,while Japanese,Korean and wstern caucasians may have other genotypes associated with HLA, this indicated there are differences in racial and regionalabout the correlation of gene polymorphism and drug-induced skin raeactions .This subject are aim to use a method of PCR-SSP to screen ten alleles including HLA - B * 1502 of uyghur and han nationalilty taken carbamazepine oxcarbazepine and lamotrigine in xinjiang to investigate the existence of key genes correlation of skin reaction in different nationalities. According to the differentiation data between nationalites, to explore whether there is a protect gene that can prevent skin reactions ; put forward predictors for adverse skin reactions before take durgs such as carbamazepine for uyghur and han nationalities.

卡马西平、奥卡西平、拉莫三嗪等药物主要治疗癫痫，由于药物结构的相似性而在临床上出现交叉反应。临床发现，服用卡马西平等药物有诱发SJS/TEN等严重皮肤反应可能，发病机制不清楚，但遗传因素是可能的原因之一。研究表明，卡马西平诱发的SJS/TEN等皮肤反应，台湾汉族人携带的HLA-B*1502 基因与之存在强相关，而日、欧美白种人则可能与HLA其他基因型有相关，提示基因多态性与药物诱发皮肤反应的相关性存在种族和地区差异。本课题在对新疆服用卡马西平等药物的维、汉患者临床观察的基础上，采用PCR-SSP法筛查HLA-B*1502 等十个HLA等位基因，研究维、汉民族中卡马西平等诱发皮肤反应与所选基因相关性，探讨维、汉民族发生皮肤反应的关键基因；根据维、汉民族间的差异化数据，探讨是否存在防止皮肤反应发生的保护基因；初步提出维、汉患者服用卡马西平等药物前针对皮肤不良反应的预测指标。

斑丘疹（maculopapule，MPE）是卡马西平、拉莫三嗪和奥卡西平等芳香环类抗癫痫药物（antiepileptic drugs，AEDs）在临床使用过程中最常发生的皮肤型药物不良反应(Cutaneous adverse drug reactions，cADRs) ，其发病机制不清楚，但遗传因素是可能的原因之一。本课题采用了第二代测序（Next generation sequencing，NGS）技术对收集的208例维吾尔族癫痫患者和201例汉族癫痫患者的HLA 等位基因进行全基因组测序，并初步提出了8个与卡马西平、拉莫三嗪和奥卡西平等任意一种芳香族AEDs诱导的新疆地区维吾尔族MPE癫痫患者相关的新的风险等位基因：HLA-A*03:01，HLA-A*03:22，HLA-B*07:02，HLA-C*07:50，HLA-C*06:02，HLA-DPA1*03:01，HLA-DPB1*51:01和HLA-DQB1*06:09；以及8个与卡马西平、拉莫三嗪和奥卡西平等任意一种芳香族AEDs诱导的新疆地区汉族MPE癫痫患者相关的新的风险等位基因：HLA-A*03:01，HLA-A*24:33，HLA-B*07:02，HLA-C*01:02，HLA-DPA1*03:01，HLA-DPB1*106:01，HLA-DPB1*17:01和HLA-DQB1* 06:09。本研究结果不仅丰富了新疆地区本地人群尤其是少数民族HLA多态性数据库，也通过初步尝试建立新疆地区维吾尔族、汉族癫痫患者服用芳香族AEDs前的参考筛选指标，为临床安全、有效使用该类药物提供理论依据。