Association between GABRG2 rs211037 polymorphism and febrile seizures: a meta-analysis
Acta Epileptologica volume 3, Article number: 5 (2021)
Emerging evidence has implied that the GABRG2 gene play a role in the mechanism of febrile seizure (FS), however, the relationship between GABRG2 rs211037 polymorphism and the risk of FS remains controversial. This meta-analysis was conducted to investigate the relationship of GABRG2 rs211037 polymorphism with the susceptibility to FS.
MEDLINE, Embase, Cochrane Library and CNKI databases were searched (until April 6, 2019) for eligible studies on the relationship between GABRG2 rs211037 polymorphism and FS. We calculated the odds ratios (ORs) by a fixed or random model with the STATA 15.0 software. Subgroup analyses for the ethnicity, the source of the control, and age and sex matching of controls were conducted.
A total of 8 studies consisting of 775 FS patients and 5162 controls were included in this study. Based on the overall data, he GABRG2 rs211037 polymorphism was not significantly associated with the risk of FS (TT + CT vs CC: OR = 0.95, 95%CI 0.64–1.41, P = 0.80). Notably, the GABRG2 rs211037 variant was significantly associated with decreased risk of FS in Asian populations (TT vs CT + CC: OR = 0.63, 95%CI 0.45–0.88, P = 0.006), but increased risk in Caucasian populations (CT vs CC: OR = 1.56, 95%CI 1.14–2.15, P = 0.006). Significant associations were also detected when healthy controls out of the whole controls were employed for comparison (TT vs CT + CC: OR = 0.59, 95% CI 0.45–0.77, P < 0.001) and when data from studies with age- and sex-matched controls were used (TT + CT vs CC: OR = 0.60, 95% CI 0.43–0.86, P = 0.001).
The GABRG2 rs211037 polymorphism may decrease the risk of FS in Asian populations, while increasing the risk in Caucasian populations. Further well-designed studies with large sample sizes are essential to verify the conclusions in other ethnicities.
Febrile seizure (FS) is a type of seizure related with fever, but the causes and mechanisms of FS remain to be determined. As the most common seizure subtype in children, FS affects 2–5% of children, especially those younger than 5 years . Although the exact pathogenesis of FS remains obscure, genetic factors may act as an important factor .
The gamma-aminobutyric acid type A (GABAA) receptor (GABAAR) contains mainly α, β and γ subunits and mediates a great many inhibitory neurotransmission in the brain [3, 4]. The γ2 subunit is vital for postsynaptic clustering and synaptic maintenance of GABAARs by affecting the kinetics of the GABAAR channels [5,6,7]. Mutations in the GABRG2 gene could produce a nonfunctioning or clipped γ protein, thereby disturbing subunit assembly, reducing the expression of surface receptor, decreasing the GABAergic inhibitory effect, and finally inducing epileptogenesis [8, 9]. Previous studies have revealed several epilepsy risk variants of GABRG2, among which the rs211037 variant has attracted much attention. The GABRG2 rs211037 variant can disturb the expression levels of the GABAAR subunits by influencing transcription, mRNA stability, and translation efficiency, resulting in varied sensitivity to extrinsic environmental signals .
The relation between GABRG2 rs211037 polymorphism and the risk of FS has been investigated in previous studies. Haerian et al. conducted a meta-analysis to investigate the relationship between the GABRG2 gene polymorphism and epilepsy, and indicated that rs211037 was associated with FS in Asians. Nevertheless, the number of included articles was relatively small, so it may be underpowered to verify the association. Although several new studies have been published recently [11,12,13,14], some important factors, including the type of control, the matching criteria of control and the consistency of Hardy-Weinberg equilibrium (HWE) were not considered in subgroup analysis. On account of the important role of the GABRG2 rs211037 polymorphisms in FS, we carried out this meta-analysis to strengthen the statistical power and further identify the association.
Literature search strategy
Studies related to the relation of GABRG2 rs211037 polymorphism with FS were searched in the MEDLINE, Embase, Cochrane Library and CNKI databases until April 6, 2019. The following search terms were used: (‘febrile seizure’), (‘GABRG2’) and (‘polymorphism’ OR ‘variant’ OR ‘mutation’). No language restriction was set on the literature search. Furthermore, we conducted a manual search from the references of reviews and eligible studies.
Inclusion and exclusion criteria
Xiaohui Yang and Jing Chi screened each eligible study independently, and Xiaosa Chi would rejudge the study if any disagreement. The inclusion criteria of publications were as follows: (1) assessing the association between GABRG2 rs211037 variants and FS; (2) genotype frequency data of both case and control groups were available; (3) having a case-control design; and (4) English or Chinese publications. Accordingly, the exclusion criteria were as follows: (1) providing insufficient genotype information; (2) animal studies or experiments in vitro; (3) family-based or linkage studies; (4) reviews and conference abstracts; and (5) case reports or lacking a control group. Besides, articles including subjects at the same hospital during overlapping times were regarded as duplications, and only the study with the largest sample size was included for analysis.
Two authors (Xiaohui Yang and Xiaomeng Wang) extracted the baseline data from the included studies seperately and repeatedly, and any discrepancies were figured out by discussion. We extracted the following information from each article: first author, year of publication, country, ethnicity of the subjects, source of controls (healthy control or patients), matching criteria of controls (age-, sex-matched or not), HWE of controls, study period, genotyping methods, quality of control, numbers of cases and controls, and frequencies of genotype.
We assessed the strength of the correlation between GABRG2 rs211037 polymorphism and the risk of FS by the pooled OR and corresponding 95% CI, using dominant model (TT + CT vs CC), recessive model (TT vs CT + CC), and other genetic models (TT vs CC, CT vs CC, and T vs C). Furthermore, subgroup-analyses were stratified by ethnicity, source of the control (non-FS or healthy control) and the matching criteria in controls (age-, sex-matched or not). We calculated the pooled OR using the Z test, and regarded P < 0.05 as statistical significance.
We used Cochran’s Q test and the I2 statistic to estimate the inter-study heterogeneity among the eligible studies, and regarded I2 ≥ 50% as statistical significance. In this condition, the random-effects model was applied to calculate the pooled OR. Otherwise, the fixed-effects model was applied. Moreover, publication bias was evaluated using visual inspection of Funnel plot which was obtained from Begg’s test. All data were calculated and analyzed with the STATA software (version 15.0; Stata Corp, College Station, Texas).
Altogether 472 potentially related articles were yielded at the initial database search, and 349 were left after duplicate removal (Fig. 1). After manual screening by titles and abstracts, 302 studies were excluded according to the exclusion criteria. Forty-seven full-text studies were used for further evaluation. Ultimately, 8 eligible studies consisting of 5937 subjects (775 FS patients and 5162 controls) were included in this study [11,12,13,14,15,16,17,18]. The detailed information of all included studies are present in Table 1. The genotype distributions of GABRG2 rs211037 polymorphism of included studies are shown in Table 2.
Quantitative data analysis
Overall, we found no significant relationship between the GABRG2 rs211037 polymorphism (TT + CT vs CC) and the risk of FS (dominant model, OR = 0.95, 95%CI 0.64–1.41, P = 0. 80, Fig. 2). Nevertheless, when stratifying the subjects by ethnicity, the GABRG2 rs211037 polymorphism (TT vs CT + CC) was significantly related to decreased risk of FS in Asian patients (recessive model, OR = 0.63, 95%CI 0.45–0.88, P = 0.006, Fig. 3). As to the Caucasian patients, the GABRG2 rs211037 polymorphism (CT vs CC) was significantly related to increased risk of FS (OR = 1.56, 95%CI 1.14–2.15, P = 0.006, Table 3).
To eliminate the potential confounding factors in the control group, we conducted stratified analyses for healthy control subjects and age-, sex-matched controls. We found a significant relation between GABRG2 rs211037 polymorphism and the susceptibility to FS when healthy controls were employed for comparison (recessive model, OR = 0.59, 95% CI 0.45–0.77, P < 0.001, Fig. 4). When analysis was performed using data from studies with age and sex matched controls, significant association was detected between the GABRG2 rs211037 variant (CT + TT vs CC) and the susceptibility to FS (dominant model, OR = 0.60, 95% CI 0.43–0.86, P = 0.005, Table 3).
The symmetrical Begg’s funnel plot indicated that there was no publication bias among included studies (Fig. 5). Quantitative evaluation by Egger’s test also demonstrated no publication bias (t = 0.70, P = 0.497).
Evidence is emerging that the GABRG2 gene is implicated in the mechanisms of FS, however, the relationship between GABRG2 rs211037 polymorphism and the risk of FS is still controversial. Previous meta-analysis studies have demonstrated that the GABRG2 rs211037 polymorphisms is significantly relative to the risk of FS, but they are limited by small sample sizes. Thus, we conducted this meta-analysis to further explore the relationship.
Different from the previous meta-analyses, we found that GABRG2 rs211037 polymorphism was not significantly related to the risk of FS using data combining all ethnicities. However, the GABRG2 rs211037 polymorphism was significantly related to decreased risk of FS in Asian populations, but increased risk of FS in Caucasian populations. This suggested that ethnicity could modify the impact of the GABRG2 gene on the risk of FS. In addition, the GABRG2 rs211037 polymorphism was associated with decreased risk of FS when healthy controls out of the whole controls were used for comparison.
The γ2 subunit is the major component of GABAAR, and its decrease is reported to affect the phasic or synaptic transmission [19,20,21,22]. Studies about cultured hippocampal neurons indicated that the relation of γ2 subunit mutations with FS may be due to the decreased expression of mutant GABAAR on the synaptic surface . In a family with febrile seizures and a GABRG2 variant R43Q, resting-state fMRI revealed increased functional connectivity within the somatosensory cortex, as compared to the age-matched controls . Besides, GABRG2 variants may affect the function and expression of several epilepsy-related genes . Thus, mutations in GABRG2 have been proposed as candidates of FS susceptibility genes. The GABRG2 rs211037 polymorphism may affect the expression of GABAAR subunits, modify the receptor composition, influence the reaction to extrinsic environmental signals, and eventually alter the neuroinflammatory pathway in FS [10, 26, 27]. In our study, the GABRG2 rs211037 polymorphism may be a protective factor for FS and play a role in the mechanisms of FS.
However, the results should be explained with caution due to the following limitations. First, relevant studies in other databases may be missed out. Second, stratified studies were not performed in Africans due to limited data. Therefore, our results need to be further verified in Africans. Third, the analysis of gene-gene and loci-loci interactions was not conducted on account of the insufficient data.
In conclusion, the current study indicated that the GABRG2 rs211037 polymorphism is significantly related to decreased risk of FS compared to healthy control. The GABRG2 rs211037 polymorphism might diversely contribute to the risk of FS in different ethnicities. Further studies are essential to verify the conclusions and reveal the underlying mechanisms.
Availability of data and materials
The datasets in this study are present in Tables.
Allele-specific polymerase chain reaction
Denaturing high-performance liquid chromatography
Matrixassisted laser desorption/ionization time of flight mass spectrometry
Mesial temporal lobe epilepsy with hippocampal sclerosis
Polymerase chain reaction-restriction fragment length polymorphism
Reverse transcription- polymerase chain reaction
a tagging single nucleotide polymorphism
Baumann RJ, Duffner PK. Treatment of children with simple febrile seizures: the AAP practice parameter. Pediatr Neurol. 2000;23:11–7.
Dube CM, Brewster AL, Baram TZ. Febrile seizures: mechanisms and relationship to epilepsy. Brain and Development. 2009;31:366–71.
Guan Z, Saraswati S, Adolfsen B, Littleton JT. Genome-wide transcriptional changes associated with enhanced activity in the Drosophila nervous system. Neuron. 2005;48:91–107.
Benarroch EE. GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology. 2007;68:612–4.
Günther U, Benson J, Benke D, Fritschy J-M, Reyes G, Knoflach F, et al. Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type a receptors. Proc Natl Acad Sci. 1995;92:7749–53.
Essrich C, Lorez M, Benson JA, Fritschy J-M, Lüscher B. Postsynaptic clustering of major GABA a receptor subtypes requires the γ2 subunit and gephyrin. Nat Neurosci. 1998;1:563.
Schweizer C, Balsiger S, Bluethmann H, Mansuy IM, Fritschy J-M, Mohler H, et al. The γ2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses. Mol Cell Neurosci. 2003;24:442–50.
Hirose S. Mutant GABA(a) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res. 2014;213:55–85.
Mulligan MK, Wang X, Adler AL, Mozhui K, Lu L, Williams RW. Complex control of GABA(a) receptor subunit mRNA expression: variation, covariation, and genetic regulation. PLoS One. 2012;7:e34586.
Wang DD, Kriegstein AR. Defining the role of GABA in cortical development. J Physiol. 2009;587:1873–9.
Abdel SS, Raham H, Karam R. GABRG2 gene polymorphisms in Egyptian children with simple febrile seizures. Indian J Pediatr. 2012;79:1514–6.
Butila AT, Zazgyva A, Sin AI, Szabo ER, Tilinca MC. GABRG2 C588T gene polymorphisms might be a predictive genetic marker of febrile seizures and generalized recurrent seizures: a case-control study in a Romanian pediatric population. Arch Med Sci. 2018;14:157–66.
Nakayama J, Hamano K, Noguchi E, Horiuchi Y, Iwasaki N, Ohta M, et al. Failure to find causal mutations in the GABA(a)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients. Neurosci Lett. 2003;343:117–20.
Ponnala S, Chaudhari JR, Jaleel MA, Bhiladvala D, Kaipa PR, Das UN, et al. Role of MDR1 C3435T and GABRG2 C588T gene polymorphisms in seizure occurrence and MDR1 effect on anti-epileptic drug (phenytoin) absorption. Genet Test Mol Biomarkers. 2012;16:550–7.
Balan S, Sathyan S, Radha SK, Joseph V, Radhakrishnan K, Banerjee M. GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenet Genomics. 2013;23:605–10.
Chou IC, Peng CT, Huang CC, Tsai JJ, Tsai FJ, Tsai CH. Association analysis of gamma 2 subunit of gamma- aminobutyric acid type a receptor polymorphisms with febrile seizures. Pediatr Res. 2003;54:26–9.
Haerian BS, Baum L, Kwan P, Cherny SS, Shin JG, Kim SE, et al. Contribution of GABRG2 polymorphisms to risk of epilepsy and febrile seizure: a Multicenter cohort study and meta-analysis. Mol Neurobiol. 2015;53:5457–67.
Kinirons P, Cavalleri GL, Shahwan A, Wood NW, Goldstein DB, Sisodiya SM, et al. Examining the role of common genetic variation in the gamma2 subunit of the GABA(a) receptor in epilepsy using tagging SNPs. Epilepsy Res. 2006;70:229–38.
Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(a) receptors. Nat Rev Neurosci. 2005;6:215–29.
Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(a) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev. 2008;60:243–60.
Sieghart W, Sperk G. Subunit composition, distribution and function of GABA-A receptor subtypes. Curr Top Med Chem. 2002;2:795–816.
Whiting PJ. GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discov Today. 2003;8:445–50.
Kang JQ, Shen W, Macdonald RL. Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. J Neurosci. 2006;26:2590–7.
Pedersen M, Kowalczyk M, Omidvarnia A, Perucca P, Gooley S, Petrou S, Scheffer IE, Berkovic SF, Jackson GD. Human GABRG2 generalized epilepsy: increased somatosensory and striatothalamic connectivity. Neurol Genet. 2019;5:e340.
Li XX, Guo SN, Liu KM, Zhang C, Chang HG, Yang WL, Rong SK, et al. GABRG2 deletion linked to genetic epilepsy with febrile seizures plus affects the expression of GABA a receptor subunits and other genes at different temperatures. Neuroscience. 2020;438:116–36.
Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(a) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci. 2005;25:7724–33.
Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet. 2011;12:683–91.
This study was supported by the National Natural Science Foundation of Shandong, China (ZR2019PH040) and the National Natural Science Foundation of China (81901321).
Ethics approval and consent to participate
Consent for publication
All authors consented to publish this study.
The authors declare no conflicts of interest.
About this article
Cite this article
Yang, X., Chi, J., Wang, X. et al. Association between GABRG2 rs211037 polymorphism and febrile seizures: a meta-analysis. Acta Epileptologica 3, 5 (2021). https://doi.org/10.1186/s42494-021-00038-0