Ngai Chuen Sin

Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese.

There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood-brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C>T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C>T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio=2.5, 95% confidence interval=1.4-4.6, P=0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations.

Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression.

Objectives Many antiepileptic drugs (AEDs) prevent seizures by blocking voltage-gated brain sodium channels. However, treatment is ineffective in 30% of epilepsy patients, which might, at least in part, result from polymorphisms of the sodium channel genes. We investigated the association of AED responsiveness with genetic polymorphisms and correlated any association with mRNA expression of the neuronal sodium channels. Methods We performed genotyping of tagging and candidate single nucleotide polymorphisms (SNPs) of SCN1A, 2A, and 3A in 471 Chinese epilepsy patients (272 drug responsive and 199 drug resistant). A total of 27 SNPs were selected based on the HapMap database. Genotype distributions in drug-responsive and drug-resistant patients were compared. SCN2A mRNA was quantified by real-time PCR in 24 brain and 57 blood samples. Its level was compared between patients with different genotypes of an SCN2A SNP found to be associated with drug responsiveness. Results SCN2A IVS7-32A>G (rs2304016) A alleles were associated with drug resistance (odds ratio=2.1, 95% confidence interval: 1.2–3.7, P=0.007). Haplotypes containing the IVS7-32A>G allele A were also associated with drug resistance. IVS7-32A>G is located within the putative splicing branch site for splicing exons 7 and 9. PCR of reverse-transcribed RNA from blood or brain of patients with different IVS7-32A>G genotypes using primers in exons 7 and 9 showed no skipping of exon 8, and real-time PCR showed no difference in SCN2A mRNA levels among genotypes. Conclusion Results of this study suggest an association between SCN2A IVS7-32A>G and AED responsiveness, without evidence of an effect on splicing or mRNA expression.

Two-stage genome-wide association study identifies variants in CAMSAP1L1 as susceptibility loci for epilepsy in Chinese

In the majority of patients, epilepsy is a complex disorder with multiple susceptibility genes interacting with environmental factors. However, we understand little about its genetic risks. Here, we report the first genome-wide association study (GWAS) to identify common susceptibility variants of epilepsy in Chinese. This two-stage GWAS included a total of 1087 patients and 3444 matched controls. In the combined analysis of the two stages, the strongest signals were observed with two highly correlated variants, rs2292096 [G] [P= 1.0 × 10(-8), odds ratio (OR) = 0.63] and rs6660197 [T] (P= 9.9 × 10(-7), OR = 0.69), with the former reaching genome-wide significance, on 1q32.1 in the CAMSAP1L1 gene, which encodes a cytoskeletal protein. We also refined a previously reported association with rs9390754 (P= 1.7 × 10(-5)) on 6q21 in the GRIK2 gene, which encodes a glutamate receptor, and identified several other loci in genes involved in neurotransmission or neuronal networking that warrant further investigation. Our results suggest that common genetic variants may increase the susceptibility to epilepsy in Chinese.

Gene-wide tagging study of association between ABCB1 polymorphisms and multidrug resistance in epilepsy in Han Chinese

AIMS It remains controversial whether polymorphisms of the multidrug resistance gene ABCB1 are associated with pharmacoresistance in epilepsy. To further study the potential association, we genotyped a broad set of tagging SNPs, and explored whether any associations were affected by other host factors. We correlated any association with cerebral mRNA expression of ABCB1. MATERIALS & METHODS A total of 12 tagging and candidate SNPs of ABCB1 were genotyped in 464 Chinese epilepsy patients (270 drug responsive, 194 drug resistant). Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. ABCB1 mRNA was quantified by real-time PCR in brain samples resected from 20 patients with drug-resistant epilepsy. Its level was compared between patients with different genotypes of ABCB1 SNPs found to be associated with drug resistance. RESULTS The intronic polymorphism rs3789243 (p = 0.009 for allele analysis) and the coding polymorphism 2677G/T/A (p = 0.02), and haplotypes containing them, were associated with drug resistance. The 2677G/T/A genotypes remained significantly associated with drug resistance after multiple logistic regression and correction for multiple comparisons. The associations with drug resistance were found in males (p = 0.004 for rs3789243 and p = 0.0007 for 2677T/A>G) but not females, and in patients with localization-related (p = 0.006 for rs3789243 and p = 0.01 for 2677T/A>G) but not idiopathic-generalized epilepsy. ABCB1 mRNA levels did not correlate with genotypes. CONCLUSION In Chinese epilepsy patients, the ABCB1 intronic polymorphism rs3789243 and the coding polymorphism 2677, and haplotypes containing them, may be associated with drug resistance, without an effect on mRNA expression. There was preliminary evidence of interactions between these polymorphisms and gender and epilepsy syndrome.

Gene-wide tagging study of the association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy

AIM To determine the association between polymorphisms of the multidrug transporter genes ABCC2, ABCC5 and ABCG2, and drug resistance in epilepsy by genotyping comprehensive sets of tagging SNPs. MATERIALS & METHODS A total of 25 tagging SNPs from ABCC2, ABCC5 and ABCG2 genes were genotyped in a total of 590 Han Chinese epilepsy patients (262 drug resistant and 328 drug responsive). Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. RESULTS Genotype distributions of all the selected SNPs were consistent with Hardy-Weinberg equilibrium. None of the polymorphisms, either genotype or allele distributions, were significantly associated with drug resistance. For each gene, no haplotypes of over 1% frequency, and that included all SNPs of the gene, were associated with drug resistance. CONCLUSION This gene-wide tagging study revealed no association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy.

Failure to detect association between polymorphisms of the sodium channel gene SCN1A and febrile seizures in Chinese patients with epilepsy

A recent study in Caucasians found an association between the single nucleotide polymorphism (SNP) of SCN1A, IVS5N +5 G>A (rs3812718), and febrile seizures (FS). We examined whether this and other tagging SNPs of SCN1A were associated with an increased risk of FS in Han Chinese. A total of 728 Han Chinese patients with focal epilepsy were recruited: 97 had a history of FS (58% male, mean age 35 ± 12 years) and 631 did not (50% male, mean age 40 ± 15 years). Genotyping was performed for IVS5N +5 G>A and seven other tagging SNPs selected from the HapMap database. Genotyping was also performed in 848 ethnically matched population controls (50% male, mean age 37 ± 17 years). There was no statistically significant difference in either allele or genotype frequency of any of the SNPs studied between epilepsy patients with and without FS, and between epilepsy patients with FS and controls. The results do not suggest that SCN1A SNPs are susceptibility factors for FS in Han Chinese.

Hepatic failure in a child with anti-epileptic hypersensitivity syndrome.

Abstract:  An 11‐year‐old boy developed severe hypersensitivity reaction to phenobarbitone resulted in fulminant hepatic failure. During the course of illness, he developed clinical features compatible with severe acute respiratory syndrome (SARS) that may have complicated the recovery of his underlying hypersensitivity reaction, which was subsequently controlled with intravenous immune globulin and corticosteroids.

Deceptive hyperbilirubinaemia in a newborn with familial lipoprotein lipase deficiency

Abstract: A rare case of familial lipoprotein lipase (LPL) deficiency in a Chinese newborn who presented with severe hyperbilirubinaemia is described. The falsely high serum bilirubin concentration was subsequently found to be a laboratory analytical error caused by interference of optical measurement of the lipaemic serum. Hypertriglyceridaemia and chylomicronaemia could be safely and effectively controlled by a fat‐restricted diet using either modified elementary milk formula fortified with protein, calories and minerals, or the commercially available special milk formula such as Monogen or Portagen. DNA sequence analysis of the patient showed a Leu252Arg mutation in exon 6 of both alleles of the LPL gene. Although the parents were unrelated, both were heterozygous carriers of the same genetic defect. Codon 252 in exon 6 appears to be a common and critical site of mutation in the LPL gene of Chinese, but this important association has not been recognized previously.