1.
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;(10):1153-66
Abstract
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. Original submitted 11 March 2013; Revision submitted 31 May 2013.
2.
Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.
Valdes, AM, Arden, NK, Vaughn, FL, Doherty, SA, Leaverton, PE, Zhang, W, Muir, KR, Rampersaud, E, Dennison, EM, Edwards, MH, et al
Arthritis care & research. 2011;(3):440-4
Abstract
OBJECTIVE To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel Na(V)1.7. METHODS Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes. RESULTS No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of β = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses. CONCLUSION We find evidence that the R1150W amino acid change in the Na(V)1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain.
3.
Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients.
Smits, JP, Eckardt, L, Probst, V, Bezzina, CR, Schott, JJ, Remme, CA, Haverkamp, W, Breithardt, G, Escande, D, Schulze-Bahr, E, et al
Journal of the American College of Cardiology. 2002;(2):350-6
Abstract
OBJECTIVES We have tested whether a genotype-phenotype relationship exists in Brugada syndrome (BS) by trying to distinguish BS patients with (carriers) and those without (non-carriers) a mutation in the gene encoding the cardiac sodium channel (SCN5A) using clinical parameters. BACKGROUND Brugada syndrome is an inherited cardiac disease characterized by a varying degree of ST-segment elevation in the right precordial leads and (non)specific conduction disorders. In a minority of patients, SCN5A mutations can be found. Genetic heterogeneity has been demonstrated, but other causally related genes await identification. If a genotype-phenotype relationship exists, this might facilitate screening. METHODS In a multi-center study, we have collected data on demographics, clinical history, family history, electrocardiogram (ECG) parameters, His to ventricle interval (HV), and ECG parameters after pharmacologic challenge with I(Na) blocking drugs for BS patients with (n = 23), or those without (n = 54), an identified SCN5A mutation. RESULTS No differences were found in demographics, clinical history, or family history. Carriers had a significantly longer PQ interval on the baseline ECG and a significantly longer HV time. A PQ interval of > or =210 ms and an HV interval > or =60 ms seem to be predictive for the presence of an SCN5A mutation. After I(Na) blocking drugs, carriers had significantly longer PQ and QRS intervals and more increase in QRS duration. CONCLUSIONS We observed significantly longer conduction intervals on baseline ECG in patients with established SCN5A mutations (PQ and HV interval and, upon class I drugs, more QRS increase). These results concur with the observed loss of function of mutated BS-related sodium channels. Brugada syndrome patients with, and those without, an SCN5A mutation can be differentiated by phenotypical differences.