Functional Variant in Complement <em>C3</em> Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

BackgroundHuman mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. Methodology/Principal FindingsA case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. Conclusions/SignificanceThe present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.背景：人类内侧颞叶癫痫（human mesial temporal lobe epilepsies, MTLE）是最常见的部分性癫痫类型，且常于婴幼儿期及儿童早期伴随热性惊厥（febrile seizures, FS）发作。多项补体基因（包括其核心组分C3）与中枢神经系统疾病存在遗传关联，且癫痫尤其是MTLE患者体内存在C3表达失调现象，这使得C3基因成为人类MTLE的优质候选易感基因。 方法/主要发现：本研究首先针对首批122例MTLE患者与196例健康对照开展C3基因的病例对照关联研究（case-control association study）。针对C3启动子区域新发现的二核苷酸重复多态性（dinucleotide repeat polymorphism）位点GF100472[(CA)8至(CA)15]构建的4种单倍型（haplotype，HAP1至HAP4），在伴有热性惊厥个人史的MTLE亚组患者（MTLE-FS+）中，经邦费罗尼校正（Bonferroni correction）后仍显示出显著关联。在独立招募的患者与对照队列中进行的重复验证分析（replication analysis）证实，携带GF100472最短长度等位基因[(CA)8]的罕见单倍型HAP4可对MTLE-FS+产生保护作用。携带GF100472中等长度(CA)11等位基因的第5种单倍型（HAP5）在对照人群中的出现频率是首段MTLE-FS+队列的4倍，且在97例单纯性热性惊厥（pure FS）的独立人群中，显示出对热性惊厥具有显著保护作用的统计学差异。在另一组148例热性惊厥患者中同样证实，(CA)11等位基因本身可对单纯性热性惊厥产生保护作用。报告基因实验（reporter gene assays）结果显示，GF100472可显著影响C3启动子活性（重复序列数量越多，转录活性越低）。综上，本研究获得的一致性遗传数据与功能分析表明，补体C3基因启动子区域这一新发现的功能性多态性，可能参与介导伴有热性惊厥史的人类MTLE以及单纯性热性惊厥的遗传易感性。 结论/意义：本研究提供了重要数据，首次表明补体系统（complement system）参与癫痫发作与癫痫的遗传易感性。