The allelic and genotypic frequencies of CYP2C9*1, *2, and *3 in white and black Brazilians are similar to those reported for other white (Caucasian) and black (African and African American) populations, respectively. Heterozygosis for CYP2C9*3, and to a lesser degree CYP2C9*2, increases the exposure to tenoxicam during single and repeated doses.
Mutations at these positions cause large effects on the kinetics of ligand association and dissociation, but they do not alter the physical interaction of ␤ with the ␣ subunit. All these data, taken together, suggest that the large extracellular loop of the maxi-K channel ␤ subunit has a restricted conformation. Moreover, they are consistent with the view that four residues appear to be important for inducing an appropriate conformation within the ␣ subunit that allows high affinity ChTX binding.
BackgroundEndometriosis is regarded as a complex and heterogeneous disease in which genetic and environmental factors contribute to the phenotype. The Vascular Endothelial Growth Factor (VEGF) plays important roles in the pathogenesis of endometriosis. The present study was aimed at investigating the contribution of VEGF polymorphisms as risk factors for the development of endometriosis. This is the first study to evaluate the combined influence of the five most common VEGF polymorphisms.MethodsThis study was conducted at two hospitals from the Brazilian public health system, and comprised 294 women submitted to laparoscopic or laparotomy surgery: 182 patients had a histologically confirmed diagnosis of endometriosis (cases), whereas 112 had no evidence of the disease (controls). The VEGF polymorphisms were determined by TaqMan real-time polymerase chain reaction. The odds ratio (OR) with their 95% confidence intervals (CI) were calculated using an unconditional logistic regression model.ResultsEndometriosis patients and controls did not differ regarding age distribution, whereas the body mass index was significantly lower in endometriosis patients, when compared with controls (23.1 ± 3.9 versus 27.3 ± 5.9, P < 0.001). The evaluation of gynecological symptoms, including dysmenorrhea, non-cyclic chronic pelvic pain, dyspareunia and infertility, indicates significantly higher prevalences among endometriosis cases. The variant allele -1154A was significantly associated with endometriosis, either considering all cases (OR: 1.90, 95% CI: 1.23–2.97), deep infiltrating endometriosis (DIE) (OR: 1.83, 95% CI: 1.16-2.90) or moderate and severe endometriosis (stages III-IV) (OR: 1.97, 95% CI: 1.21-3.19). No significant differences were found in allele or genotype distributions of the –2578C > A, -460 T > C, +405G > C and +936C > T polymorphisms between endometriosis cases and controls. A total of six haplotypes were inferred derived from four polymorphisms (-2578C > A, -460 T > C, -1154G > A and +405G > C). There was a protective association between CCGG haplotype and endometriosis, either considering all cases (OR: 0.36, 95% CI: 0.15–0.86), DIE (OR: 0.37 95% CI: 0.15 – 0.90) or stages III-IV (OR: 0.35 95% CI: 0.13 – 0.95).ConclusionsThe present results indicate a positive association between VEGF -1154G > A and the risk of developing endometriosis, whereas the CCGG haplotype may be protective against the development of disease.
BackgroundCyclooxygenase-2 (COX-2) is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Here, we evaluate the association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene (PTGS2) and the occurrence of breast cancer among Brazilian women.MethodsThe study was conducted prospectively in two steps: First, we screened the promoter region and three fragments of the 3'-untranslated region of PTGS2 from 67 healthy Brazilians to identify SNPs and to select those with a minor allele frequency (MAF) of at least 0.10. The MAF of these selected SNPs was further characterized in 402 healthy volunteers to evaluate potential differences related to heterogeneous racial admixture and to estimate the existence of linkage disequilibrium among the SNPs. The second step was a case-control study with 318 patients and 273 controls designed to evaluate PTGS2 genotype- or haplotype-associated risk of breast cancer.ResultsThe screening analysis indicated nine SNPs with the following MAFs: rs689465 (0.22), rs689466 (0.15), rs20415 (0.007), rs20417 (0.32), rs20419 (0.015), rs5270 (0.02), rs20424 (0.007), rs5275 (0.22) and rs4648298 (0.01). The SNPs rs689465, rs689466, rs20417 and rs5275 were further studied: Their genotypic distributions followed Hardy-Weinberg equilibrium and the MAFs were not affected by gender or skin color. Strong linkage disequilibrium was detected for rs689465, rs20417 and rs5275 in the three possible pairwise combinations. In the case-control study, there was a significant increase of rs5275TC heterozygotes in cases compared to controls (OR = 1.44, 95% CI = 1.01-2.06; P = 0.043), and the haplotype formed by rs689465G, rs689466A, rs20417G and rs5275C was only detected in cases. The apparent association with breast cancer was not confirmed for rs5275CC homozygotes or for the most frequent rs5275C-containing haplotypes.ConclusionsOur results indicate no strong association between the four most frequent PTGS2 SNPs and the risk of breast cancer.
Background Piroxicam (P), a widely prescribed NSAID, is eliminated by hydroxylation catalyzed by CYP2C9 enzyme, which is encoded by the polymorphic CYP2C9 gene. Methods Single oral doses (20 mg) of P were given to healthy, adult Brazilian volunteers with distinct CYP2C9 genotypes. The plasma P concentration and the P‐induced changes in the activity of cyclooxygenase 1 (COX‐1; ex‐vivo formation of tromboxane B2 in blood) were measured from zero to 240h. Results P′s oral CL/F was significantly reduced, and both AUC and t1/2 were increased in carriers of variant alleles *2 and *3 in heterozygosis or homozygosis. There was no difference in these pharmacokinetic parameters between genotypes *1/*2 and *1/*3. Cmax was not affected by CYP2C9 genotype. (see Table) The AUC for the inhibitory effect of P on the activity of COX‐1, expressed relative to the pre‐dosing value (units.h) increased with the number of variant CYP2C9 alleles, from 110± 23 (*1/*1, n= 5) to 172± 44 (combined *1/*2 and *1/*3, n =12) and to 208 ‐ 223 (combined *2/*2 and *3/*3, n =2). Conclusion We confirmed our previous observation with tenoxicam that both the variant alleles CYP2C9*2 and *3 significantly influence the pharmacokinetics of oxicam NSAIDs. We also show that both alleles *2 and *3 are associated with the intensity of the inhibitory effect of P on COX‐1. Clinical Pharmacology & Therapeutics (2005) 77, P62–P62; doi: Pharmacokinetics of piroxicam in healthy Brazilians Parameter *1/*1 (n = 14) *1/*2 (n = 9) *1/*3 (n = 10) *2/*2 (n = 1) *2/*3 (n = 1) *3/*3 (n = 1) Cmax(mgL−1)2.4 ± 0.72.2 ± 0.42.5 ± 0.41.61.92.6AUC0‐240h(mg.L−1)136 ± 34220 ± 77221 ± 67197186501CL/F (L.h−1)0.14 ± 0.030.09 ± 0.030.08 ± 0.020.090.070.01t1/2 (h)40.3 ± 9.872.8 ± 19.980.1 ± 24.794.6118.5674.1
Cyclooxygenase-2 (COX-2) overexpression is associated with worse prognosis in breast cancer. COX-2 is encoded by a polymorphic gene, called PTGS2, and its expression may be genetically influenced. In this article, we investigate the association between PTGS2 haplotypes and histopathological parameters with prognostic value on the clinical outcome of breast cancer. The study involved 606 women under current treatment for non-metastatic breast cancer. Patients were genotyped for rs689465, rs689466, rs20417, and rs5275, and their haplotypes were inferred. The distribution of PTGS2 genotypes and haplotypes was evaluated according to histopathological categorical groups used for prognostic determination of low/intermediate versus high risk of tumor recurrence. Our results indicate positive associations between variant genotypes of rs689465 and estrogen receptor negativity (OR: 1.59, 95% CI: 1.04-2.44, P: 0.02) or HER2 positivity (OR: 1.79, 95% CI: 1.00-3.18, P: 0.03), and between variant genotypes of rs20417 and estrogen receptor negativity (OR: 1.75, 95% CI: 1.15-2.57, P: 0.005), progesterone receptor negativity (OR: 1.56, 95% CI: 1.09-2.22, P: 0.01) or HER2 positivity (OR: 1.80, 95% CI: 1.04-3.13, P: 0.02). In contrast, variant genotypes of rs689466 are negatively associated with estrogen receptor negativity (OR: 0.57, 95% CI: 0.33-0.98, P: 0.03). A total of eight haplotypes were inferred, and there was a significant difference in their distribution as a function of tumor size (P: 0.011), estrogen receptor status (P: 0.018), and HER2 status (P: 0.025). PTGS2 haplotype *7 (formed by rs689465G, rs689466A, rs20417C, and rs5275T) is positively associated with higher tumor size (OR: 3.72, 95% CI: 1.19-11.22, P: 0.006), estrogen receptor negativity (OR: 2.43, 95% CI: 0.97-5.98, P: 0.032), progesterone receptor negativity (OR: 2.58, 95% CI: 1.05-6.39, P: 0.02), and HER2 positivity (OR: 4.17, 95% CI: 1.19-14.44, P: 0.007). Our results suggest that PTGS2 haplotype *7 may contribute to higher growth of untreated breast cancer and that PTGS2 haplotypes need to be considered in the characterization of breast cancer prognosis.
Background: Ion channels are involved in the control of membrane potential (ψ) in a variety of cells. The maintenance of ψ in human T lymphocytes is essential for T-cell activation and was suggested to depend mostly on the voltage-gated Kv1.3 channel. Blockage of Kv1.3 inhibits cytokine production and lymphocyte proliferation in vitro and suppresses immune response in vivo. T lymphocytes are a heterogeneous cell population and the expression of Kv1.3 varies among cell subsets. Oxonol diBA-C4-(3) was used to determine ψ by flow cytometry. The presence of distinct T cell subsets was evaluated by immunophenotyping techniques and the contribution of Kv1.3 channels for the maintenance of ψ was investigated using selective blockers.
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