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Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09–2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16–2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06–2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan. [ABSTRACT FROM AUTHOR]

Ion channels play important roles in signal transduction and in the regulation of the ionic composition of intra- and extracellular fluids. Mutations in ion channels have long been thought to be responsible for some forms of hearing loss. Defects in KCNQ4, a voltage-gated potassium channel, are a cause of nonsyndromic sensorineural deafness type 2, an autosomal dominant form of progressive hearing loss. We present data of mutation analysis of KCNQ4 from 185 unrelated Taiwanese probands with nonsyndromic hearing loss. The analysis revealed three novel KCNQ4 mutations and many polymorphisms. The prevalence of KCNQ4 gene mutations in this study was 1.62% (3/185). The mutations include a missense mutation (F182L) and two silent mutations (R216R and T501T). The F182L missense mutation was located in the S3 domain of KCNQ4. The F182 residue of KCNQ4 is highly conserved in KCNQ4 among various species and is less conserved in all members of the KCNQ family. In addition, although R216R is a silent mutation and does not alter the content of amino acid residue, the neural network prediction system revealed that it can potentially create a novel splice donor site during transcription. This mutation might affect the protein structure of KCNQ4 and consequently the normal function of the K+ channel. Our data provide the first comprehensive analysis of the KCNQ4 gene in Taiwanese patients with nonsyndromic deafness. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Background: Influence of folate/homocysteine conversion is considered to be important in the pathogenesis of Parkinson''s disease (PD). However, association of the folate metabolic pathway gene polymorphisms with PD susceptibility remains unclear. Methods: To test this possibility in PD, we conducted a hospital-based case-control study constituting 211 patients and 218 age- and sex-matched controls of ethnic Chinese in Taiwan. Genotyping assay was performed to screen for polymorphisms of the methylenetetrahydrofolate reductase (MTHFR C677T), methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR A1049G and C1783T) genes and assess the association between these genotype polymorphisms and PD risk using logistic regression analysis. Results: Of these four non-synonymous polymorphisms, the MTRR 1049GG variant was significantly associated with PD susceptibility (OR=3.17, 95%CI=1.08–9.35). Furthermore, we stratified our patients based on the MTHFR 677TT genotype in different strata, a significant association between the joint effect of polymorphisms and PD risk was observed in those patients whose genotypes were MTRR A1049G/MTR A2756G or MTRR C1783T/MTR A2756G (P <0.05). Conclusion: Our findings provide support for the synergistic effects of polymorphisms in the folate metabolic pathway genes in PD susceptibility; the increased PD risk would be more significant in carriers with the polymorphisms of MTHFR, MTR, and MTRR genes. [Copyright &y& Elsevier]

Abstract: Background: Hypothetic mechanism of the individual vulnerability to oxidative stress through metabolism of environmental xenobiotics and genotypic polymorphisms has been considered to promote the development of Parkinson''s disease (PD). In this case-control study, we determined the role of manganese-containing superoxide dismutase (MnSOD) and NAD(P)H: quinone oxidoreductase 1 (NQO1) genes in PD risk in a population with high prevalence of pesticide exposure. Methods: From southwestern region of Taiwan, we enrolled 153 patients with idiopathic PD and 155 healthy control subjects matched for age, sex and origin. Detailed questionnaires of face-to-face interviews among these subjects were collected. PCR-based restriction fragment length polymorphism (RFLP) assays were used to determine the genotypes of MnSOD (−9 T>C) and NQO1 (609 C>T) genes. Results: Exposure to pesticides associated with PD was significant among patients with an increased odds ratio (OR) of 1.69 (95%CI, 1.07–2.65), and this association remained significant after adjustment for age, sex, and cigarette smoking (aOR=1.68, 95%CI, 1.03–2.76, P =0.023). Considering genetic factors, there were no significant differences in frequencies of both genotypes of MnSOD and NQO1 polymorphisms between PD patients and the control subjects (P >0.05). However, this difference in genotype distribution was significant among subjects who had been exposed to pesticide, with aOR of 2.49 (95%CI, 1.18–5.26, P =0.0072) for MnSOD C allele and aOR of 2.42 (95%CI, 1.16–4.76, P =0.0089) for NQO1 T allele, respectively. Moreover, among subjects exposed to pesticide, the combined MnSOD/NQO1 variant genotype was significantly associated with a 4.09-fold increased risk of PD (95%CI, 1.34–10.64, P =0.0052). Conclusion: Susceptible variants of MnSOD and NQO1 genes may interact with occupational pesticide exposure to increase PD risk in southwestern Taiwanese. [Copyright &y& Elsevier]

Abstract: Hyperactivation of N-methyl-d-aspartate receptors (NMDARs) leads to neuronal excitotoxicity and is suggested to play a role in many brain disorders, including Alzheimer''s disease and schizophrenia. However, the association between polymorphisms in the genes that code for NMDAR subunits, N-methyl-d-aspartate 1 and 2B (GRIN1 and GRIN2B) and Parkinson''s disease (PD) remains unclear. In a hospital-based case–control study of PD, DNA samples were collected from 101 PD patients and 205 healthy controls. Genotyping assays were used to screen for polymorphisms in the GRIN1 (rs2301364 T > C, rs28489906 T > C, and rs4880213 T > C) and GRIN2B (C366G, C2664T, and rs1805476 T > G) genes, and logistic regression analysis was then used to assess the association between these single nucleotide polymorphisms (SNPs) and PD susceptibility. None of the 6 SNPs were significantly associated with PD risk on their own. However, in conjunction with putative low-risk genotypes for the GRIN1 gene, the GRIN2B C366G variant was significantly associated with reduced PD risk compared with the homozygous genotype 366CC (OR=0.38, 95%CI=0.17–0.93, P =0.033). A synergistic effect on risk reduction was observed in subjects who carried multiple polymorphisms of GRIN1 and the GRIN2B C366G polymorphism (OR=0.78, 95%CI=0.59–1.02, P trend =0.073). Our results suggest that polymorphisms in the GRIN1 and GRIN2B genes may serve as potential biomarkers for a reduced risk of PD among the Chinese population in Taiwan. [Copyright &y& Elsevier]

Abstract: Background: γ-Glutamyl carboxylation, a reaction essential for the biosynthesis of vitamin K-dependent coagulation factors, requires the participation of the γ-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKORC1), and NAD(P)H:quinone oxidoreductase (NQO1). We evaluated the role of these genotype polymorphisms in patients with large-artery atherosclerotic stroke. Methods: In this hospital-based case–control study, 117 patients who were categorized as having large-artery atherosclerotic stroke and 115 age- and gender-matched controls were recruited. Genotyping determination for the GGCX1 (Gln325Arg), NQO1 (Pro187Ser), and VKORC1 (rs9923231) polymorphisms was performed. The associations of genotype with ischemic stroke (IS) risk were examined. Results: A higher genotypic frequency of NQO1 C609T was found in the controls than in the patients, manifesting a 0.47-fold risk reduction in IS (95% CI=0.25–0.87). A tendency toward a reduced IS risk was statistically significant in those subjects who carried a greater number of the NQO1, GGCX, and VKORC1 polymorphisms (aOR=0.58, P trend =0.005). The synergistic effect of multiple genes on risk reduction was more significant in a subset of patients who were not alcoholics and who were non-smokers (P <0.05). Conclusions: Compartmentation of coagulation factor metabolism may account for the preferential role of NQO1, GGCX, and VKORC1 polymorphisms to lower the risk for large-artery atherosclerotic stroke. [Copyright &y& Elsevier]