Association study between interleukin 1 beta gene and epileptic disorders: a HuGe review and meta-analysis.

From the ¹Consultorio de Neurogenética, Centro de Epilepsia, División Neurología, Hospital Ramos Mejía, CEFYBO, CONICET, Buenos Aires, Argentina; ²Residencia de Neurología, División Neurología, Hospital Ramos Mejía, Buenos Aires, Argentina; ³Centro de Epilepsia, División Neurología, Hospital Ramos Mejía, CEFYBO, CONICET, Buenos Aires, Argentina; ⁴Laboratorio de Neurogenética, Servicio de Neurología, Sanatorio Franchín, Buenos Aires, Argentina.

Marcelo Kauffman, Urquiza 609 (1221), Buenos Aires, Argentina. E-mail: marcelokauffman@gmail.com.

Disclosure: The authors declare no conflict of interest.

A supplementary appendix table is available via the ArticlePlus feature at www.geneticsinmedicine.org . Please go to the February issue and click on the ArticlePlus link posted with the article in the Table of Contents to view this material.

Received for publication July 3, 2007. Accepted for publication October 2, 2007.

Previous studies have examined the association of a single nucleotide polymorphism at the promoter region of interleukin 1B (IL-1β-511T) with temporal lobe epilepsy and febrile seizures susceptibility, but those studies have been inconclusive. Published studies up to March 2007 of temporal lobe epilepsy, febrile seizures and the IL-1β-511T single nucleotide polymorphism were identified by searches of Medline and Embase databases. Meta-analysis of temporal lobe epilepsy and febrile seizures case-control data were performed to assess the association of IL-1β-511T with temporal lobe epilepsy, temporal lobe epilepsy with hippocampal sclerosis, febrile seizures, and other epileptic disorders. Pooled odds ratios (OR) were estimated by means of a genetic-model-free approach. The quality of the included studies was assessed by a score. The results show a modest association (OR, 1.48; 95% confidence interval, 1.09-2.00; P = 0.01) between the IL-1β-511T polymorphism and temporal lobe epilepsy with hippocampal sclerosis.

The interleukin (IL)-1 family accounts for three genes: IL-1α, IL-1β (proinflammatory cytokines), and their inhibitor, the IL-1 RA (IL-1β receptor antagonist). All three genes are located in the long arm of chromosome 2. Clinical studies show that IL-1 is a significant mediator of inflammatory diseases in vivo, as exemplified by patient responses to IL-1 inhibitors.(1,2) Three biallelic polymorphisms in IL-1β have been most frequently evaluated for their association with diverse conditions (reviewed in Refs. 3-5) besides epilepsy; all three result from C-to-T transitions at positions -511, -31, or +3954 from the transcriptional start site.(4) The IL-1β-511 (rs16944) single nucleotide polymorphism (SNP) leads to an increased expression of the encoded protein as a result of enhanced gene transcription.(6) However, this activity seems to be dependent on the haplotype context of the promoter region of IL-1β. Chen et al.(7) demonstrated that the IL-1β-511T allele strongly enhanced the transcription of the IL-1β gene in the context of the IL-1β-31C allele. Conversely, the enhancement is significantly lower in the context of the IL-1β-31T allele.(7) These findings highlight the importance of understanding the haplotype structure of populations used for genetic studies. Nevertheless, this overexpression of IL-1β might contribute to the development of febrile seizures (FS) and eventually to subsequent hippocampal neuronal damage.

We therefore performed a systematic review of the association between IL-1β-511 SNP and TLE or FS with the following objectives: first to estimate allele frequencies, second to estimate if there is an effect of this polymorphism on TLE and FS susceptibility, and if so, to determine its magnitude and third, to assess for methodological bias that could account for the differences in the reported studies.

FS accounts for the most common human convulsive event.(26) They affect approximately 2-5% of all children in North America and Europe.(27) They are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical age range of 6 months to 6 years. Although they are considered as a benign seizure disorder, up to 7% of affected children develop unprovoked seizures (epilepsy) later during life.(27) Twin and family studies point to an important genetic component in the etiology of FS.(28,29)

Based on a series of 100 patients who had surgery for intractable TLE, Falconer et al.(30) observed that a significant proportion of those with HS had antecedents of prolonged FS in early childhood (30% in the HS group compared with 6% in the group without HS). However, prospective studies failed to confirm this relationship.(31)

Because it is well known that a rapid rise of fever or high body temperatures during an infectious disease can trigger seizures in individuals who are prone to FS,(31) genes encoding proteins involved in the regulation of inflammatory processes and fever are plausible candidate genes in the elucidation of the molecular mechanisms of FS and TLE. Inflammation may also be involved in secondary epileptogenesis in TLE.(32) This is supported by some studies that have demonstrated the presence of chronic inflammation in the hippocampus.(33)

Search strategy
The MEDLINE and EMBASE databases were searched with no language restrictions from their inception to March 30, 2007. The search strategy was ([interleukin 1β OR IL-1β OR interleukin 1] AND [temporal lobe epilepsy OR epilepsy OR seizures OR febrile seizures] AND [polymorph$ OR mutation$ OR variant$ OR genotype$]). All references cited in these studies and published reviews were reviewed to identify additional works not indexed by the databases selected. When there were multiple publications from the same study group, the most complete and recent results were used.

Inclusion criteria
Eligible studies had to meet all the following criteria: (a) published in a peer-reviewed journal and independent studies using original data; (b) provided sufficient data to calculate the odds ratio (OR) with confidence interval (CI) and P value; (c) investigated the IL-1β-511T polymorphism; (d) described the genotyping method or provided reference to it; (e) included patients with a diagnosis of an epileptic syndrome; (f) used healthy individuals as controls. Authors were contacted in cases in which there were queries regarding their studies.

Data extraction
Two investigators (M.K. and D.G.M.) independently extracted the following data from each publication: author; country of origin; selection and characteristics of cases and controls; demographic information; racial descent of the study population; numbers of eligible and genotyped cases and controls; and numbers of cases and controls for each IL-1β-511 genotype. Disagreements were resolved by consensus.

Quality score assessment
Methodologic quality was independently assessed by two reviewers (M.K. and D.G.M.), according to a set of predefined criteria (Supplementary Table 1), based on the scale of Thakkinstian et al.(34) Disagreements were resolved by consensus. Scores ranged from 0 (lowest) to 10 (highest).

Second, for the controls in each study, Hardy-Weinberg equilibrium (HWE) was assessed using the exact test.

Third, a Q test for heterogeneity was performed separately for three odds ratios (ORs), that is, T/T versus C/C (OR1), C/T versus C/C (OR2), and T/T versus C/T (OR3). If there was heterogeneity on at least one of these odds ratios, we estimated the overall gene effect by use of logistic regression with the random-effects model as described by Bagos and Nikolopoulos(36); otherwise, logistic regression with the fixed-effect model as described by Thakkinstian et al.(37) was used to estimate the overall gene effect.

Fourth, if the main effect of the genotype was statistically significant, further comparisons of OR1, OR2, and OR3 were explored. These pairwise differences were used to indicate the most appropriate genetic model as follows.

* Recessive model: if OR1 = OR3 ≠ 1 and OR2 = 1.

* Dominant model: if OR1 = OR2 ≠ 1 and OR3 = 1.

* Overdominant model: if OR2 = 1/OR3 ≠ 1 and OR1 = 1.

* Codominant model: if OR1 > OR2 >1 and OR1 > OR3 >1

* (or OR1 < OR2 <1, and OR1 < OR3 <1).

Finally, using the most appropriate genetic model to collapse the three genotypes into two groups, the pooled estimate of risk was obtained using the fixed effect inverse variance method.

Publication bias was assessed using Egger's and Begg-Matzumdar tests. Statistical analysis was done with Stata, version 9 (Stata Corporation, College Station, TX). P < 0.05 was considered statistically significant, except for heterogeneity, Egger's and Begg's tests, in which a level of 0.10 was used.

Study inclusion and characteristics
The combined search yielded 42 references. After overlapping references and those that did not meet inclusion criteria were discarded, 14 references were retained. These references were then filtered to ensure conformity to inclusion criteria. In two overlapping reports(8,12) from Kanemoto et al., we retained the one(8) with the largest and more recent sample size. Healthy controls included in the studies of Virta et al.(9) and Peltola et al.(38) were the same, thus they were counted once. Finally, 13 references met our criteria for inclusion (Table 1). Four of them analyzed the association with TLE,(10,13,39,40) four did it with FS,)9,14,41,42) two included patients with temporal and extratemporal partial epilepsy,(8,38) one reference included FS and TLE patients,(43) one study included patients with TLE, extratemporal partial epilepsy and generalized epilepsy,(44) and a further study included patients with FS and patients with epilepsy not typified.(11) Therefore, the studies compared a total of 1866 epilepsy cases and 1930 controls. Within the population of epileptic patients, there were a total of 610 TLE cases and 560 FS cases. The studies differed in the type of FS included. Four studies included simple and complex FS,(9,14,41,42) whereas two did not identify the type of FS included.(11,43) There were also differences in the analysis of TLE cases, in which four studies included only TLE with HS cases.(10,13,40,44) The quality of studies ranged from 0 to 8, out of a possible score of 10. Five studies were conducted in Asia,(8,11,14,39,42) seven in Europe,(9,13,38,40,41,43,44) and one in the USA.(10) Results of HWE analysis for controls were reported in four studies.(10,14,40,44) Our calculation of HWE for the rest of included studies showed that one report deviated from HWE.(41) In all studies, investigators used the same DNA genotyping method.

click to view

Table 1  Genotype frequencies in epileptic disorders cases and controls from the 13 studies included in the analysis of IL-1β-511 polymorphism

Pooled prevalence of IL-1β-511T in control populations
The thirteen included studies estimated the T-allele frequency. Eight of them were performed in Caucasians and five in Asians. There was heterogeneity across the studies (P = 0.002) when data from Caucasians and Asians were analyzed together. However, there was not marked heterogeneity across the studies in Asians (P = 0.97) nor across the studies in Caucasians (P = 0.25). Pooled allele T frequencies were 0.40 (95% CI, 0.37-0.43) in all populations, 0.37 (95% CI, 0.36-0.38) in Caucasians and 0.47 (95% CI, 0.465-0.475) in Asians (P < 0.001 for the difference in proportions).

IL-1β-511T polymorphism and epileptic disorders risk
Heterogeneity was checked for OR1 (T/T vs. C/C), OR2 (C/T vs. C/C), and OR3 (T/T vs. C/T). Results indicated heterogeneity for OR2 and OR3 but not for OR1 (for OR1: χ211 = 16.39 P = 0.127; for OR2: χ211 = 25.14 P = 0.009; for OR3: χ211 = 25.14 P = 0.009). Hence, these 12 studies were pooled by use of logistic regression with the random-effects model as described by Bagos and Nikolopoulos.(36) The overall gene effect was not significant, with the estimated OR1 and OR2, being 1.159 (95% CI, 0.949-1.415) and 1.049 (95% CI, 0.903-1.219), respectively. There was no evidence of publication bias (P > 0.5 for Begg and Egger tests).

IL-1β-511T polymorphism and febrile seizures risk
Heterogeneity was checked for OR1 (T/T vs. C/C), OR2 (C/T vs. C/C), and OR3 (T/T vs. C/T). Results indicated no heterogeneity for the three OR (for OR1: χ25 = 6.64 P = 0.249; for OR2: χ25 = 8.85 P = 0.115; for OR3: χ25 = 6.38 P = 0.271). Therefore, logistic regression with the fixed-effect model as described by Thakkinstian et al.(37) was used to assess the overall gene effect. The overall gene effect was not significant (likelihood ratio [LR] = 1.25, P = 0.53), with the estimated OR1, OR2 and OR3 being 1.16 (95% CI, 0.841-1.614), 1.14 (95% CI, 0.876-1.482) and 1.02 (95% CI, 0.747-1.397), respectively. There was no evidence of publication bias (P > 0.85 for Begg and Egger tests).

IL-1β-511T polymorphism and temporal lobe epilepsy risk
Heterogeneity was checked for OR1 (T/T vs. C/C), OR2 (C/T vs. C/C), and OR3 (T/T vs. C/T). Results indicated no heterogeneity for the three OR (for OR1: χ26 = 3.36 P = 0.762; for OR2: χ26 = 6.29 P = 0.392; for OR3: χ26 = 2.71 P = 0.844). Therefore, logistic regression with the fixed-effect model as described by Thakkinstian et al.(37) was used to assess the overall gene effect. The overall gene effect was not significant (LR = 2.69, P = 0.26), with the estimated OR1, OR2, and OR3 being 1.16 (95% CI, 0.861-1.576), 0.92 (95% CI, 0.733-1.149) and 1.27 (95% CI, 0.952-1.691), respectively. There was no evidence of publication bias (P > 0.6 for Begg and Egger tests).

IL-1β-511T polymorphism and temporal lobe epilepsy with hippocampal sclerosis risk
Heterogeneity was checked for OR1 (T/T vs. C/C), OR2 (C/T vs. C/C), and OR3 (T/T vs. C/T). Results indicated no heterogeneity for the three OR (for OR1: χ25 = 4.83 P = 0.437; for OR2: χ25 = 5.18 P = 0.394; for OR3: χ25 = 6.39 P = 0.27). Therefore, logistic regression with the fixed-effect model as described by Thakkinstian et al.(37) was used to assess the overall gene effect. The LR test indicated that the overall gene effect was significant (LR = 6.72, P = 0.03), with the estimated OR1, OR2, and OR3 being 1.41 (95% CI, 1.01-1.96), 0.92 (95% CI, 0.72-1.19) and 1.52 (95% CI, 1.11-2.08), respectively. These estimates suggest a recessive effect of the T allele for this phenotype. Therefore, T/T was compared with C/T and C/C genotypes combined. Figure 1 presents the fixed-effect pooled OR for this comparison. Overall, a significant increase in TLEHS risk for T allele homozygotes was observed. There was no evidence of publication bias (P > 0.5 for Begg and Egger tests).

click to view

Figure 1 : Forest plots of OR with 95% CIs of temporal lobe epilepsy with hippocampal sclerosis associated with the IL-1β-511T polymorphism. The OR (black squares), with the size of the square inversely proportional to its variance, and 95% CIs (horizontal lines). Pooled results (unshaded black diamond). The studies are ordered by publication year.

Kanemoto et al.(12) and Virta et al.(9) were the first to report an association between the IL-1β-511T polymorphism and TLEHS and FS, respectively. However, these findings were not replicated by others raising controversy about the real role of this genetic variant in the susceptibility to develop these diseases. Indeed, this apparent contradiction is very often found in the field of genetics of complex disorders. Discrepant findings may be due to multiple causes such as differences in the populations analyzed, difficulties with the phenotype definition, or designs with low power to detect genetics effects that necessarily are small.(45) The effect of common alleles is of a small magnitude; thus studies with many hundreds of subjects are required to detect them. This difficulty could be solved, at least in part, by doing a systematic review of the literature and thereby performing a meta-analysis.

Limitations
The data set analyzed is of a relatively small magnitude; thus, sensitivity analysis could not be done limiting the robustness of our findings. The quality of the studies is heterogeneous, with many studies receiving low quality scores as judged by the criteria in Appendix Table 1. This concern is of particular importance for the reports that assessed the association with FS. Not all investigators provided appropriate descriptions of the criteria for the identification and selection of cases, a few of them did so for controls, and only one study mentioned that genotyping was performed under blinded conditions.(39) Furthermore, because variables not completely analyzed such as age, ethnicity, and gender could bias results, future studies and meta-analyses with a greater number of cases and designs of better quality are needed to provide a better estimate of the effect of this polymorphism in the development of these disorders.

Biological mechanism
IL-1β-511T seems to be a functional SNP(6) and IL-1β is increasingly recognized as a cytokine with a significant role in different epileptogenic mechanisms.(46,47) Accordingly, carriers of the IL-1β-511T allele are higher producers of IL-1β(6) than carriers of the IL-1β-511C allele. Furthermore, IL-1β, among other pro-inflammatory cytokines, seems to influence the electrophysiology of neurons.(48) For example, in the kainate-induced animal epilepsy model, the application of IL-1β prolonged hippocampal seizures by enhancing glutamatergic neurotransmission.(49) Moreover, IL-1β has been shown to contribute to an enhanced neuronal hyperexcitability and a decreased seizure threshold.(50) Furthermore, FS are often triggered by a rapid rise in body temperature(50,51); therefore, endogenous pyrogens, like IL-1, plausibly could contribute to the development of FS.

M.K. has a scholarship from CONICET. S.K. is member of National Scientific Council Research Career (CONICET).

1. Camp NJ, Cox A, di Giovine FS, McCabe D, et al. Evidence of a pharmacogenomic response to interleukin-l receptor antagonist in rheumatoid arthritis. Genes Immun 2005;6:467-471.
2. Mrak RE, Griffin WS. Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging 2001;22:903-908.
3. Huynh-Ba G, Lang NP, Tonetti MS, Salvi GE. The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review. J Clin Periodontol 2007;34:305-317.
4. Wang P, Xia HH, Zhang JY, Dai LP, et al. Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 2007;120:552-562.
5. Shirts BH, Wood J, Yolken RH, Nimgaonkar VL. Association study of IL-10, IL-1beta, and IL-1RN and schizophrenia using tag SNPs from a comprehensive database: suggestive association with rs16944 at IL-1beta. Schizophr Res 2006;88:235-244.
6. Wen AQ, Wang J, Feng K, Zhu PF, et al. Effects of haplotypes in the interleukin 1beta promoter on lipopolysaccharide-induced interleukin 1beta expression. Shock 2006;26:25-30.
7. Chen H, Wilkins LM, Aziz N, Cannings C, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet 2006;15:519-529.
8. Kanemoto K, Kawasaki J, Yuasa S, Kumaki T, et al. Increased frequency of interleukin-1beta-511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion. Epilepsia 2003;44:796-799.
9. Virta M, Hurme M, Helminen M. Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures. Pediatr Neurol 2002;26:192-195.
10. Buono RJ, Ferraro TN, O'Connor MJ, Sperling MR, et al. Lack of association between an interleukin 1 beta (IL-1beta) gene variation and refractory temporal lobe epilepsy. Epilepsia 2001;42:782-784.
11. Chou IC, Tsai CH, Hsieh YY, Peng CT, et al. Association between polymorphism of interleukin-1beta-511 promoter and susceptibility to febrile convulsions in Taiwanese children. Acta Paediatr 2003;92:1356.
12. Kanemoto K, Kawasaki J, Miyamoto T, Obayashi H, et al. Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol 2000;47:571-574.
13. Ozkara C, Uzan M, Tanriverdi T, Baykara O, et al. Lack of association between IL-1beta/alpha gene polymorphisms and temporal lobe epilepsy with hippocampal sclerosis. Seizure 2006;15:288-291.
14. Kira R, Torisu H, Takemoto M, Nomura A, et al. Genetic susceptibility to simple febrile seizures: interleukin-1beta promoter polymorphisms are associated with sporadic cases. Neurosci Lett 2005;384:239-244.
15. Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003;361:865-872.
16. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet 2001;29:306-309.
17. Abou-Sleiman PM, Hanna MG, Wood NW. Genetic association studies of complex neurological diseases. J Neurol Neurosurg Psychiatry 2006;77:1302-1304.
18. Engel J, Jr, Wiebe S, French J, Sperling M, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American epilepsy Society and the American Association of Neurological Surgeons. Neurology 2003;60:538-547.
19. Jackson J Case of epilepsy with tasting movements and dreamy state: very small patch of softening in the left uncinate gyrus. Brain 1898;21:580-590.
20. Penfield W. temporal lobe epilepsy. Br J Surg 1954;41:337-343.
21. Wieser HG. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:695-714.
22. Cendes F, Lopes-Cendes I, Andermann E, Andermann F. Familial temporal lobe epilepsy: a clinically heterogeneous syndrome. Neurology 1998;50:554-557.
23. Berkovic SF, McIntosh A, Howell RA, Mitchell A, et al. Familial temporal lobe epilepsy: a common disorder identified in twins. Ann Neurol 1996;40:227-235.
24. Briellmann RS, Torn-Broers Y, Jackson GD, Berkovic SF. seizures in family members of patients with hippocampal sclerosis. Neurology 2001;57:1800-1804.
25. Tan NC, Mulley JC, Berkovic SF. Genetic association studies in epilepsy: the truth is out there. Epilepsia 2004;45:1429-1442.
26. Rantala H, Tarkka R, Uhari M. Preventive treatment for recurrent febrile seizures. Ann Med 2000;32:177-180.
27. Vestergaard M, Pedersen CB, Sidenius P, Olsen J, et al. The long-term risk of epilepsy after febrile seizures in susceptible subgroups. Am J Epidemiol 2007;165:911-918.
28. Kjeldsen MJ, Corey LA, Solaas MH, Friis ML, et al. Genetic factors in seizures: a population-based study of 47,626 US, Norwegian and Danish twin pairs. Twin Res Hum Genet 2005;8:138-147.
29. Pal DK, Kugler SL, Mandelbaum DE, Durner M. Phenotypic features of familial febrile seizures: case-control study. Neurology 2003;60:410-414.
30. Falconer MA. Mesial temporal (Ammon's horn) sclerosis as a common cause of epilepsy. Aetiology, treatment, and prevention. Lancet 1974;2:767-770.
31. Nakayama J, Arinami T. Molecular genetics of febrile seizures. epilepsy Res 2006;70 (Suppl 1):S190-S198.
32. Crespel A, Coubes P, Rousset MC, Brana C, et al. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res 2002;952:159-169.
33. Bernardino L, Ferreira R, Cristovao AJ, Sales F, et al. Inflammation and neurogenesis in temporal lobe epilepsy. Curr Drug Targets CNS Neurol Disord 2005;4:349-360.
34. Thakkinstian A, D'Este C, Eisman J, Nguyen T, et al. Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study. J Bone Miner Res 2004;19:419-428.
35. Thakkinstian A, McEvoy M, Minelli C, Gibson P, et al. Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 2005;162:201-211.
36. Bagos PG, Nikolopoulos GK. A method for meta-analysis of case-control genetic association studies using logistic regression. Stat Appl Genet Mol Biol 2007;6:Article 17.
37. Thakkinstian A, McElduff P, D'Este C, Duffy D, et al. A method for meta-analysis of molecular association studies. Stat Med 2005;24:1291-1306.
38. Peltola J, Keranen T, Rainesalo S, Hurme M. Polymorphism of the interleukin-1 gene complex in localization-related epilepsy. Ann Neurol 2001;50:275-276.
39. Jin L, Jia Y, Zhang B, Xu Q, et al. Association analysis of a polymorphism of interleukin 1 beta (IL-1 beta) gene with temporal lobe epilepsy in a Chinese population. Epilepsia 2003;44:1306-1309.
40. Heils A, Haug K, Kunz WS, Fernandez G, et al. Interleukin-1beta gene polymorphism and susceptibility to temporal lobe epilepsy with hippocampal sclerosis. Ann Neurol 2000;48:948-950.
41. Haspolat S, Baysal Y, Duman O, Coskun M, et al. Interleukin-1alpha, interleukin-1beta, and interleukin-1Ra polymorphisms in febrile seizures. J Child Neurol 2005;20:565-568.
42. Matsuo M, Sasaki K, Ichimaru T, Nakazato S, et al. Increased IL-1beta production from dsRNA-stimulated leukocytes in febrile seizures. Pediatr Neurol 2006;35:102-106.
43. Tilgen N, Pfeiffer H, Cobilanschi J, Rau B, et al. Association analysis between the human interleukin 1beta (-511) gene polymorphism and susceptibility to febrile convulsions. Neurosci Lett 2002;334:68-70.
44. Cavalleri GL, Lynch JM, Depondt C, Burley MW, et al. Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here? Brain 2005;128:1832-1840.
45. Zondervan KT, Cardon LR. The complex interplay among factors that influence allelic association. Nat Rev Genet 2004;5:89-100.
46. Vezzani A, Conti M, De Luigi A, Ravizza T, et al. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci 1999;19:5054-5065.
47. Zhu G, Okada M, Yoshida S, Mori F, et al. Effects of interleukin-1beta on hippocampal glutamate and GABA releases associated with Ca2+-induced Ca2+ releasing systems. epilepsy Res 2006;71:107-116.
48. Heida JG, Pittman QJ. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia 2005;46:1906-1913.
49. Dube C, Vezzani A, Behrens M, Bartfai T, et al. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol 2005;57:152-155.
50. Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med 2006;12:817-823.
51. Berg AT. Are febrile seizures provoked by a rapid rise in temperature? Am J Dis Child 1993;147:1101-1103.