Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy.
OBJECTIVE
The etiopathogenesis of temporal lobe epilepsy (TLE) and its subgroups - mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and TLE with antecedent febrile seizures (TLE-FS) - is poorly understood. It has been proposed that the water channel aquaporin-4 (AQP4) and the potassium channel Kir4.1 (KCNJ10 gene) act in concert to regulate extracellular K(+) homeostasis and that functional alterations of these channels influence neuronal excitability. The current study was designed to identify variants of the AQP4 and KCNJ10 genes associated with TLE and subgroups of this condition.


METHODS
We included 218 Norwegian patients with TLE and 181 ethnically matched healthy controls. An association study was established in which all TLE patients were compared with healthy controls. Additionally, subgroups of 56 MTLE-HS patients were compared with 162 TLE patients without HS, and 102 TLE-FS patients were compared with 105 TLE without FS.


RESULTS
We found eight single SNPs, seven in KCNJ10 and one between KCNJ10 and KCNJ9, associated with TLE-FS (nominal p-values from 0.009 to 0.041). Seven of the SNPs segregate into one large haplotype block expanding from KCNJ10 to KCNJ9, including the region interposed those genes. One haplotype was overrepresented in the TLE-FS cases (nominal p-value 0.014). These results were confirmed by explorative multivariate analysis indicating that a combination of SNPs from KCNJ10, the region between KCNJ10 and KCNJ9, and the AQP4 gene is associated with TLE-FS. For the TLE cohort as a whole, explorative multivariate analysis indicated a combination of SNPs from the KCNJ10 and AQP4 genes in association with TLE.


CONCLUSIONS
Variations in the AQP4 and the KCNJ10/KCNJ9 region are likely to be associated with TLE, particularly TLE-FS, supporting the suggestion that perturbations of water and K(+) transport are involved in the etiopathogenesis of TLE.
Heuser
Kjell
K
Department of Neurology, Rikshospitalet University Hospital, Oslo, Norway. kjell.heuser@rikshospitalet.no
Nagelhus
Erlend A
EA
Taubøll
Erik
E
Indahl
Ulf
U
Berg
Paul R
PR
Lien
Sigbjørn
S
Nakken
Sigve
S
Gjerstad
Leif
L
Ottersen
Ole Petter
OP
D000328:Adult; D000368:Aged; D051401:Aquaporin 4 / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000145:classification* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012598:Sclerosis / Q000209:etiology; D055815:Young Adult; D000098854:Kcnj10 Channel
C496030:AQP4 protein, human; D051401:Aquaporin 4; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying