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Fulltext GABRG2 rs211037 polymorphism and epilepsy: a systematic review and meta-analysis

Haerian BS, Baum L

Seizure, 2013 Jan;22(1):53-8.
PMID: 23140995 DOI: 10.1016/j.seizure.2012.10.007

PURPOSE: The gamma-aminobutyric acid A receptor, gamma 2 (GABRG2) gene encodes the GABRγ2 protein, which has been implicated in susceptibility to epilepsy. Several studies have examined a possible link between the exonic GABRG2 rs211037 locus and susceptibility to febrile seizure (FS) and idiopathic generalized epilepsy (IGE), however results have been inconclusive. We therefore performed a systematic review and meta-analysis to examine whether this polymorphism is associated with FS or IGE.
METHODS: Eight studies comprising 1871 epilepsy patients and 1387 controls, which evaluated association of the GABRG2 rs211037 polymorphism with susceptibility to epilepsy, were included in this meta-analysis. Meta-analysis was carried out separately for FS and IGE.
RESULTS: Meta-analysis showed a significant association between this polymorphism and susceptibility to FS in a codominant (TT vs. CC, OR 0.47, 95% CI 0.30-0.73, p=0.0008 and TT vs. CT, OR 0.59, 95% CI 0.42-0.83, p=0.003) and dominant (OR 0.54, 95% CI 0.39-0.75, p=0.0002) genetic models, influenced by two studies with small sample size. Neither allele nor genotype association was observed with IGE.
CONCLUSION: This study showed significant association of GABRG2 rs211037 with susceptibility to FS, caused by two studies with small sample sizes, however the possibility of false positive results due to the effect of significant studies for FS cannot be excluded. Future studies with larger sample sizes of these patients are suggested to verify the results.
SCN1A IVS5N+5 polymorphism and response to sodium valproate: a multicenter study

Haerian BS, Baum L, Tan HJ, Kwan P, Raymond AA, Saruwatari J, et al.

Pharmacogenomics, 2012 Oct;13(13):1477-85.
PMID: 23057548 DOI: 10.2217/pgs.12.127

Approximately 30% of epilepsy patients do not response to antiepileptic drugs (AEDs). The functional SCN1A IVS5N+5 polymorphism may play a role in response to some AEDs. The purpose of this study was to examine this hypothesis in a cohort study of Malaysian and Hong Kong Chinese epilepsy patients on sodium valproate (VPA) monotherapy and in a meta-analysis.
SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis

Haerian BS, Baum L, Kwan P, Tan HJ, Raymond AA, Mohamed Z

Pharmacogenomics, 2013 Jul;14(10):1153-66.
PMID: 23859570 DOI: 10.2217/pgs.13.104

Aim: Approximately a third of newly diagnosed epilepsy patients do not respond to antiepileptic drugs (AEDs). Evidence suggests that low penetrance variants in the genes of drug targets such as voltage-gated sodium channels may be involved in drug responsiveness. To examine this hypothesis, we compared data from two epilepsy cohorts from Malaysia and Hong Kong, as well as a meta-analysis from published data.

Materials & methods: Genotype analysis of 39 polymorphisms located in the SCN1A, SCN2A and SCN3A genes was performed on 1504 epilepsy patients from Malaysia and Hong Kong who were receiving AEDs. Meta-analysis was performed for pooled data of SCN1A rs3812718 and rs2298771, and SCN2A rs17183814 polymorphisms.

Results: Our data from the Hong Kong and Malaysia cohorts showed no significant allele, genotype and haplotype association of polymorphisms in the SCN1A, SCN2A, and SCN3A genes with drug responsiveness in epilepsy. This finding was supported by a meta-analysis for SCN1A rs3812718 and rs2298771, and for SCN2A rs17183814 polymorphisms.

Conclusion: Our comprehensive study suggests that common polymorphisms in SCN1A, SCN2A and SCN3A do not play major roles in influencing response to AEDs.
ABCC2 rs2273697 and rs3740066 polymorphisms and resistance to antiepileptic drugs in Asia Pacific epilepsy cohorts

Sha'ari HM, Haerian BS, Baum L, Saruwatari J, Tan HJ, Rafia MH, et al.

Pharmacogenomics, 2014 Mar;15(4):459-66.
PMID: 24624913 DOI: 10.2217/pgs.13.239

To examine the relevance of ABCC2 polymorphisms to drug responsiveness in epilepsy cohorts from the Asia Pacific region.
Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis

Haerian BS, Baum L, Kwan P, Cherny SS, Shin JG, Kim SE, et al.

Mol Neurobiol, 2016 10;53(8):5457-67.
PMID: 26452361 DOI: 10.1007/s12035-015-9457-y

Gamma-aminobutyric acid receptor (GABA-A) is the most common receptor of fast synaptic inhibition in the human brain. Gamma protein encoded by the GABRG2 gene is one of the subunits of the GABA-A receptor, which plays an essential role in the function of this receptor. Several studies have identified various febrile seizure (FS) and epilepsy risk variants of GABRG2 gene in different populations, but some others did not support these results. The aim of this case-control study is to investigate whether GABRG2 polymorphisms contribute to susceptibility for FS and epilepsy in pooled data of three cohorts, from Malaysia (composed of Malay, Chinese, and Indian), Hong Kong, and Korea. Furthermore, the pooled dataset of these cohorts with previous reports were meta-analyzed for determining the risk effect size of the rs211037 polymorphism on FS and symptomatic epilepsy (SE). The rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750 polymorphisms were genotyped in the 6442 subjects (1729 epilepsy and 4713 controls). Results of the case-control study showed associations between rs211037 and the risk of SE in the pooled data from all cohorts (T vs. C, p = 3 × 10(-5), and TT vs. CC, p = 2 × 10(-5)) and the risk of partial seizure in the combined data of Malaysia and Hong Kong (both T vs. C and TT vs. CC, p = 2 × 10(-6)). The rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes were also associated with susceptibility to SE in Chinese. Meta-analysis of all Asians identified association between rs211037 and FS and SE (T vs. C, p = 4 × 10(-4), and p = 4 × 10(-3), respectively). In conclusion, rs211037 alone may be a risk factor for FS, partial seizure, and SE, and in linkage disequilibrium with rs210987 can contribute to FS and SE in Asians, particularly in Chinese.
Association of BDNF Polymorphisms with the Risk of Epilepsy: a Multicenter Study

Sha'ari HM, Haerian BS, Baum L, Tan HJ, Rafia MH, Kwan P, et al.

Mol Neurobiol, 2016 07;53(5):2869-2877.
PMID: 25876511 DOI: 10.1007/s12035-015-9150-1

Epilepsy is a common neurological disease characterized by recurrent unprovoked seizures. Evidence suggested that abnormal activity of brain-derived neurotrophic factor (BDNF) contributes to the pathogenesis of epilepsy. Some previous studies identified association between genetic variants of BDNF and risk of epilepsy. In this study, this association has been examined in the Hong Kong and Malaysian epilepsy cohorts. Genomic DNA of 6047 subjects (1640 patients with epilepsy and 4407 healthy individuals) was genotyped for rs6265, rs11030104, rs7103411, and rs7127507 polymorphisms by using Sequenom MassArray and Illumina HumanHap 610-Quad or 550-Duo BeadChip arrays techniques. Results showed significant association between rs6265 T, rs7103411 C, and rs7127507 T and cryptgenic epilepsy risk (p = 0.00003, p = 0.0002, and p = 0.002, respectively) or between rs6265 and rs7103411 and symptomatic epilepsy risk in Malaysian Indians (TT vs. CC, p = 0.004 and T vs. C, p = 0.0002, respectively) as well as between rs6265 T and risk of cryptogenic epilepsy in Malaysian Chinese (p = 0.005). The Trs6265-Crs7103411-Trs7127507 was significantly associated with cryptogenic epilepsy in Malaysian Indians (p = 0.00005). In conclusion, our results suggest that BDNF polymorphisms might contribute to the risk of epilepsy in Malaysian Indians and Chinese.
Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti-seizure medications

Mullan KA, Anderson A, Shi YW, Ding JH, Ng CC, Chen Z, et al.

Epilepsia, 2022 Feb 16.
PMID: 35170024 DOI: 10.1111/epi.17182

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA-B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value.
METHODS: We performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM-induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity.
RESULTS: In the primary analysis, nine variants reached genome-wide significance (p
Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy

Baum L, Haerian BS, Ng HK, Wong VC, Ng PW, Lui CH, et al.

Hum Genet, 2014 May;133(5):651-9.
PMID: 24337656 DOI: 10.1007/s00439-013-1405-1

High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r (2) = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.
Fulltext Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4

Ma RC, Hu C, Tam CH, Zhang R, Kwan P, Leung TF, et al.

Diabetologia, 2013 Jun;56(6):1291-305.
PMID: 23532257 DOI: 10.1007/s00125-013-2874-4

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.
METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p