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

Abstract

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.

Complement system biomarkers in epilepsy

“…Eleven complement analytes were selected for this study, guided by reference to previous studies of complement biomarkers in epilepsy which have described increased serum levels or gene expression of C3, C4, C1q, iC3b and terminal complement complex (TCC), and availability of reagents and in-house assays [23,24,26,28,30]. The concentrations of nine analytes: iC3b, C1q, C3, C4, Properdin, Factor B (FB), Factor H (FH), C1 inhibitor (C1inh), and TCC were measured using established in-house enzyme-linked immunosorbent assays (ELISA) ( Table 2).…”

“…Complement activation in the CNS is increasingly recognised to be associated with exacerbation and progression of tissue injury in degenerative and inflammatory diseases [21,22]. Dysregulation of the complement system in epilepsy has been observed both in human and animal studies [23][24][25][26][27]. For example, sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioural and electrographic seizures as well as neurotoxicity, suggesting a direct role for the complement system in epileptogenesis [28].…”

Complement system biomarkers in first episode psychosis

“…The marker set was chosen to interrogate classical (C1q, iC3b, C3, C4), alternative (Properdin, FB, FH, iC3b) and terminal (TCC) activation pathways. Selected markers have been implicated in pathophysiology of mood disorders such as schizophrenia (Hakobyan et al, 2005;Mayilyan et al, 2008) and bipolar affective disorders (Akcan et al, 2017), and/or neurological and neurodegenerative disorders such as Alzheimer's disease (Kolev et al, 2009), Parkinson's disease (Loeffler et al, 2006), multiple sclerosis (Ingram et al, 2012) and epilepsy (Aronica et al, 2007;Jamali et al, 2010). CPR was measured because of its widely accepted use as a benchmark of inflammatory state.…”

Genetic variability in glutamic acid decarboxylase genes: Associations with post-traumatic seizures after severe TBI

“…Although studies suggest that genetic susceptibility contributes to the development of seizure disorders (Cavalleri et al, 2007; Jamali et al 2010) and treatment response (Ebid 2007; Hung et al, 2005; Kwan et al, 2007), little has been studied in the area of genetic susceptibility to PTS. Previous work in our lab has shown that genetic variation in the adenosine A1 receptor is associated with susceptibility to PTS (Wagner et al 2010).…”