【摘要】 目的 研究癫痫耐药与全外显子组基因单核苷酸多态性的相关性。方法 将就诊于本院的癫痫患者按照队列法分为癫痫耐药组和单药有效组。收集患者的病史以及实验室检查结果，观察患者充分治疗超过12个月后的发作情况。通过对12例极端病例(6例3药耐药患者vs. 6例单药有效且处于减药阶段的患者)进行全外显子测序，筛选候选基因，进一步在癫痫耐药组和单药有效组中进行候选基因多态性检测验证，探究基因多态性与癫痫耐药的相关性。结果 560例患者中，癫痫耐药组153例、单药有效组407例。癫痫单药有效组和耐药组的年龄中位数分别为19和25岁，体重中位数分别为50和55 kg;上述指标在2组间比较在统计学上差异均有统计学意义(均P<0.05)。在癫痫耐药组和单药有效组中，结构性病因占比分别为55.56%和45.46%;传染性病因分别为3.92%和2.21%;免疫性病因分别为3.27%和1.23%;代谢和遗传性病因分别为5.88%和11.30%;存在2种病因的分别为1.96%和1.23%。在癫痫耐药组和单药有效组中，存在意识障碍的患者占比分别为56.21%和39.07%;初始用药方案为二代抗癫痫药物患者的占比分别为50.98%和65.46%;存在局灶性皮层发育不良患者的占比分别为10.46%和2.95%;存在海马硬化的患者占比分别为15.03%和9.58%;存在缺血缺氧性脑病的患者占比分别为3.92%和1.47%;存在脑部血管畸形的患者占比分别为4.58%和3.93%;存在颅脑外伤的患者占比分别为1.31%和3.44%;存在脑部肿瘤的患者占比分别为3.92%和2.21%;存在多种病理学改变的患者占比分别为1.96%和0.98%;存在非癫痫相关改变的患者占比分别为23.53%和29.48%。基线信息显示，患者的年龄、体重、病因、发作时意识障碍与否、初始用药方案以及影像学结果与癫痫耐药相关(P<0.05,P<0.001)。纳入102个候选单核苷酸多态性(SNPs),在560例癫痫患者中展开基因分型检测与关联分析，共发现5个SNP与癫痫耐药相关。同时纳入临床因素与遗传因素，多因素logistic回归分析显示，海马硬化、局灶性皮层发育不良、缺血缺氧性脑病、发作时伴有意识障碍、SCN2A rs17183814 GG以及SPATA31 rs1919128 GA基因型是癫痫耐药的风险因素(SCN2A rs17183814:P=0.027;SPATA31 rs1919128:P=0.014)。结论 SCN2A及SPATA31基因多态性与癫痫耐药相关，SCN2A rs17183814 GG以及SPATA31 rs1919128 GA基因型患者更容易出现癫痫耐药。更多还原

【Abstract】 Objective To investigate the association between drug resistant epilepsy(DRE) and single nucleotide polymorphisms(SNPs) in whole-exome sequencing(WES). Methods Patients with epilepsy,who visited in our hospital,were enrolled in this study and divided into a drug-resistant group and a monotherapy-effective group based on treatment outcomes. Baseline demographic characteristics,medical history and laboratory test results were collected. Seizure outcomes were observed after more than 12 months under adequate treatment. WES was performed on 12 extreme cases(6 patients with resistant to three antiepileptic drugs vs. 6 patients effectively treated with monotherapy and undergoing dose reduction) to identify candidate SNPs. These candidate SNPs were then validated in the larger cohort to explore the association with DRE. Results A tota of 560 patients were enrolled,153 were DRE group and 407 were monotherapy-effective group. The median age in the monotherapy-effective group and the drug-resistant group was 19 years old and 25 years old,respectively; the median weight were50 kg and 55 kg,respectively. All these differences between the two groups were statistically significant(all P < 0. 05);the proportion of structural etiology was 55. 56% in the drug-resistant group and 45. 46% in the monotherapy-effective group; the proportion of infectious etiology were 3. 92% and 2. 21%; the proportion of immune etiology were3. 27% and 1. 23%; the proportion of metabolic and genetic etiology were 5. 88% and 11. 30%; the proportion of dual etiologies were 1. 96% and 1. 23%; the proportion of patients with impaired consciousness were 56. 21% and39. 07%; the proportion of second-generation antiseizure medication as initial medication regimen were 50. 98% and65. 46%; the proportion of malformation of cortical development were 10. 46% and 2. 95%; the proportion of hippocampal sclerosis were 15. 03% and 9. 58%; the proportion of hypoxic-ischemic encephalopathy were 3. 92%and 1. 47%; the proportion of vascular malformation were 4. 58% and 3. 93%; the proportion of traumatic brain injury were 1. 31% and 3. 44%; the proportion with brain tumor were 3. 92% and 2. 21%; the proportion with dual pathologies were 1. 96% and 0. 98%; the proportion of abnormal nonepileptogenic were 23. 53% and 29. 48%.Baseline information showed statistically significant differences in age, weight, etiology, presence of impaired awareness,initial medication regimen and neuroimaging results(P < 0. 05,P < 0. 001). 102 candidate SNPs were selected for genotyping and association analysis in larger cohort including 560 patients. 5 SNPs were identified to be significantly associated with DRE. Multivariate logistic regression incorporating both clinical and genetic factors revealed that hippocampal sclerosis,malformation of cortical development,hypoxic-ischemic,presence of impaired awareness,as well as the SCN2A rs17183814 GG and SPATA31 rs1919128 GA genotypes were risk factors for drug resistance(SCN2A rs17183814 GG: P = 0. 027; SPATA31 rs1919128 GA: P = 0. 014). Conclusion SCN2A rs17183814 and SPATA31 rs1919128 were found to be associated with drug resistance. Carriers of the GG genotypes of SCN2A rs17183814 and GA genotype of SPATA31 rs1919128 are more likely to develop DRE.更多还原