Association of serotonin transporter promoter (5-HTTLPR) and intron 2 (VNTR-2) polymorphisms with treatment response in temporal lobe epilepsy
Introduction
Epilepsy is common chronic neurological disorder. The majority of patients suffer from temporal lobe epilepsy (TLE). Neurobiological mechanisms that contribute to TLE remain unclear. Animal and human studies investigated contribution of the serotonergic (5-HT) system in the neurobiology of TLE (Theodore, 2003). Earlier studies showed that genetic epilepsy-prone rats have reduced hippocampal 5-HT receptor density (Dailey et al., 1992, De Sarro et al., 1996, Statnick et al., 1996, Salgado-Commissariat and Alkadhi, 1997) and that impairment of serotonergic activity may enhance seizure severity (Jobe et al., 1999). Serotonin-induced anticonvulsant effect was mostly mediated by hippocampal 5-HT1A receptors (Salgado-Commissariat and Alkadhi, 1997, Lu and Gean, 1998). Recent human studies demonstrated decreased 5-HT1A receptor binding in the ictal onset and ictal spreading temporal lobe regions (Merlet et al., 2004), midbrain raphe and thalamus (Toczek et al., 2003, Giovacchini et al., 2005, Hasler et al., 2007), in mesial and neocortical TLE (Fedi et al., 2001). Decreased availability of 5-HT1A receptors highly correlates with the degree of epileptogenicity of cortical areas, as shown by intracranial recordings (Merlet et al., 2004). Thus, serotonergic system dysfunction may have an important role in neurobiology of epileptogenicity and seizure severity in TLE subjects.
5-HT transporter (5-HTT) is a transmembrane protein responsible for re-uptake of 5-HT from the synaptic cleft (Lesch and Mossner, 1998). 5-HTT is encoded by a single copy gene (SLC6A4) which contains two common polymorphisms: a 44 base pair (bp) insertion/deletion in the promoter region (5-HTT gene linked polymorphic region, 5-HTTLPR) and a 17 bp variable number of tandem repeats in the second intron (VNTR-2). It was demonstrated that long (L) and short (S) variants of the 5-HTTLPR differentially modulate transcription of the 5-HTT gene, with the L variant being more efficient in a recessive manner (Lesch et al., 1996). Similarly, 12-repeat allele of the VNTR-2 intron was shown to have stronger enhancer-like properties than shorter alleles (MacKenzie and Quinn, 1999). We have previously shown a combined effect of 5-HTTLPR and VNTR-2 polymorphisms on the level of 5-HTT gene expression, with the highest expression in the group with two “high-expressing” genotypes (L/L 12/12), approximately 20% lower in the group with one “low-expressing” genotype and 50% lower in the group with “low-expressing” genotypes at both loci (Hranilovic et al., 2004).
5-HTT genetic variations have been found to affect basal cerebral metabolic activity in limbic structures in normal population (Graff-Guerrero et al., 2005) and was observed to be associated with depression (Caspi et al., 2003), schizophrenia (Hranilovic et al., 2000), and suicidal behavior (Hranilovic et al., 2003). This is the first study to our knowledge that showed association of the combination of high-expressing genotypes of 5-HTT gene and seizure factors in the patients with TLE.
Section snippets
Patients
We recruited 101 consecutive patients with video/EEG confirmed TLE at the Zagreb Epilepsy Center, during 2007–2009. Clinical data included age, gender, seizure factors (age of epilepsy onset, seizure frequency, epilepsy duration, time to initial diagnosis, epileptic region lateralization) and number of antiepileptic drugs (AEDs), education, employment and marital status. Subjects with hippocampal sclerosis, but no other focal structural lesion shown on the epilepsy protocol with 1.5 T MRI in the
Results
We found that TLE patients with a combination of homozygotic L and homozygotic 12-repeat 5-HTT genotypes have significantly higher seizure frequency. The mean seizure frequency in TLE patients carrying L/L and 12/12 genotypes (group A, n = 7, in Fig. 1) was significantly higher than in the group with L/L 10/10, L/L 10/12, S/S 12/12 and S/L 12/12 genotypes, p < 0.005 (group B, n = 56) or in the group with “no L/L, no 12/12” genotypes, p < 0.006 (group C, n = 34), or when the L/L 12/12 group was compared
Discussion
In this study we found association of the combination of transcriptionally more efficient (homozygotic L and homozygotic 12-repeat) 5-HTT genotype with poorer response to optimal medical treatment in TLE patients. These patients also have shorter periods of seizure freedom.
Previous studies suggested a role of the serotonin transporter gene in the etiology of TLE using association analysis of the 5-HTT gene in TLE patients (Manna et al., 2007) or 5-HTT gene variation in refractory mesial TLE
Acknowledgements
This work was supported by Epilepsy Foundation grant to HH and Croatian Ministry of Science, Education and Sport project to BJ.
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