Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures
Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures
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DOI：
10.1371/journal.pone.0012740
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发表时间：
2010-09-16
期刊：
影响因子：
3.7
通讯作者：
Szepetowski, Pierre
中科院分区：
文献类型：
--
作者：
Jamali, Sarah;Salzmann, Annick;Szepetowski, Pierre
背景：人类内侧颞叶癫痫(MTLE)是最常见的部分性癫痫，在婴幼儿和儿童早期经常出现发热性癫痫(FS)。几个补体基因，包括其中心成分C3与中枢神经系统疾病的遗传关联，以及C3基因在癫痫和MTLE中的存在，特别是在MTLE中，使其成为很好的候选人类MTLE的C3基因。方法/主要发现：对122例MTLE患者和196名对照进行了C3基因的病例对照关联研究。在有FS(MTLE-FS+)个人病史的MTLE患者亚组中，包括新发现的C3启动子区二核苷酸重复多态GF100472在内的四种单倍型(HAP1~4)在Bonferroni校正后有显著关联。对独立患者和对照的复制分析证实，这种罕见的HAP4单倍型包含GF100472[(CA)8]的最小长度等位基因，对MTLE-FS+具有保护作用。GF100472携带中等大小(CA)11等位基因的第5个单倍型(HAP5)在对照组中的频率是MTLE-FS+第一个队列的4倍，在97个纯FS的独立人群中显示出高度统计学意义的保护作用。一致地，在第二组148名FS患者中，(CA)11等位基因本身对纯FS具有保护作用。报告基因分析表明，GF100472显著影响C3启动子的活性(重复次数越多，转录活性越低)。总之，一致的遗传数据和功能分析表明，补体C3基因启动子的一个新发现的功能多态性可能参与了有FS病史的人类MTLE和单纯FS的遗传易感性。结论：本研究首次提供了补体系统参与癫痫发作和癫痫遗传易感性的重要数据。
Background: Human 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 Findings: A 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/Significance: The 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.