Two four-marker haplotypes on 7q36.1 region indicate that the potassium channel gene HERG1 (KCNH2, Kv11.1) is related to schizophrenia: a case control study

<p>Abstract</p> <p>Background</p> <p>The pathobiology of schizophrenia is still unclear. Its current treatment mainly depends on antipsychotic drugs. A leading adverse effect of these medications is the acquired long QT syndrome, which results from the blockade of cardiac HERG1 channels (human ether-a-go-go-related gene potassium channels 1) by antipsychotic agents. The HERG1 channel is encoded by <it>HERG1 </it>(<it>KCNH2</it>, <it>Kv11.1</it>) gene and is most highly expressed in heart and brain. Genetic variations in <it>HERG1 </it>predispose to acquired long QT syndrome. We hypothesized that the blockade of HERG1 channels by antipsychotics might also be significant for their therapeutic mode of action, indicating a novel mechanism in the pathogenesis of schizophrenia.</p> <p>Methods</p> <p>We genotyped four single nucleotide polymorphisms (SNPs) in 7q36.1 region (two SNPs, rs1805123 and rs3800779, located on <it>HERG1</it>, and two SNPs, rs885684 and rs956642, at the 3'-downstream intergenic region) and then performed single SNP and haplotype association analyses in 84 patients with schizophrenia and 74 healthy controls after the exclusion of individuals having prolonged or shortened QT interval on electrocardiogram.</p> <p>Results</p> <p>Our analyses revealed that both genotype and allele frequencies of rs3800779 (c.307+585G>T) were significantly different between populations (<it>P </it>= 0.023 and <it>P </it>= 0.018, respectively). We also identified that two previously undescribed four-marker haplotypes which are nearly allelic opposite of each other and located in chr7:150225599-150302147bp position encompassing <it>HERG1 </it>were either overrepresented (A-A-A-T, the at-risk haplotype, <it>P </it>= 0.0007) or underrepresented (C-A-C-G, the protective haplotype, <it>P </it>= 0.005) in patients compared to controls.</p> <p>Conclusions</p> <p>Our results indicate that the potassium channel gene <it>HERG1 </it>is related to schizophrenia. Our findings may also implicate the whole family of HERG channels (HERG1, HERG2 and HERG3) in the pathogenesis of psychosis and its treatment.</p

Association of a polymorphism of the ecNOS gene with myocardial infarction in a subgroup of Turkish MI patients

In this study we examined a possible association between a 27 base pair (bp)-repeat polymorphism in intron 4 of the ecNOS gene and myocardial infarction (MI) in a subgroup of the Turkish population. We compared MI and control groups for the frequencies of the ecNOS alleles and their genotypes. The frequency of the ecNOS 4a/a and 4a/b genotypes was found to be significantly higher in the MI group than in the control group. Interestingly, the frequency of the ecNOS 4a/b polymorphism was found to be significantly higher in the selected MI group (patients with no known secondary risk factors) than in the control and non-selected MI group. We found that the patients with MI had the frequency of the a/a genotype 4.3%, of the a/b genotype 26.6% and the b/b genotype 69.1%, The controls, however, showed only 0.6% for a/a, 18.0% for a/b and 81.4% for the b/b genotype (P<0.001; &chi;(2)=13.626). In this study, we show that myocardial infarction is associated with one subtype of ecNOS gene polymorphism

Association of MDR1 (C3435T) polymorphism and resistance to carbamazepine in epileptic patients from turkey

Background and Aims: We investigated the prevalence of this multidrug resistance 1 gene (MDR1) polymorphism in drug-responsive versus drug-resistant epilepsy patients treated with carbamazepine (CBZ), which is a substrate of this protein. Methods: We genotyped the C3435T variant of MDR1 in 97 patients treated with CBZ monotherapy who had been on stable doses for more than 1 month. Our control group included 174 healthy individuals. Plasma CBZ concentrations were also measured using fluorescence polarization immunoassay. Results: We could not demonstrate any statistically significant relationship with the genotypes among drug-resistant patients (n = 44). The frequency of the homozygous mutant (TT) genotype was 15% in drug-responsive patients, 11.3% in drug-resistant patients and 25.8% in the control group. We also did not observe any significant correlation between the presence of a specific allele and CBZ plasma level/dose index. Conclusion: Our study did not support any significant association between the MDR1 (C3435T) polymorphism and resistance to CBZ in epilepsy patients from Turkey. Copyright (C) 2007 S. Karger AG, Basel

Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD

AbstractIn this cross-sectional controlled study, we aimed to investigate the role of polymorphisms of the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) genes on pulmonary hypertension (PH) in patients with chronic obstructive pulmonary disease (COPD). Forty-two (41 male, 1 female, mean age: 62±7 years) COPD patients and 40 (all male, mean age: 60±8 years) healthy controls were included. Respiratory function tests, arterial blood gases, and echocardiographic examinations were performed. ACE and eNOS genotypes were determined using PCR.The ACE and eNOS genotype distribution was not significantly different between COPD patients and controls. On comparing pulmonary artery pressures in different eNOS genotypes, the mean pulmonary artery pressure (Ppa) in patients with the BB genotype was significantly higher than in patients with the nonBB genotypes (41.3±17.7mmHg vs. 27.3±11.2mmHg, P=0.02). However, there was no difference in ACE genotype distributions between COPD patients with and without pulmonary hypertension. In stepwise linear regression analysis for predicting pulmonary artery pressure, PaO2 and polymorphism of eNOS gene were found to be independent variables.In conclusion, BB-type polymorphism of the eNOS gene has been associated with PH in addition to hypoxemia. However, ACE gene polymorphism was not found to be associated with PH