Matrix metalloproteinases (MMPs) as well as their inhibitors (TIMPs) play a crucial role in controlling extracellular matrix turnover and have recently been associated with atherosclerosis, myocardial and vascular injury. Moreover, the genetic variability of MMP genes has been suggested to play an important role in vascular remodeling and age-related arterial stiffening. This study aims to describe associations of 14 selected polymorphisms in genes for MMPs and TIMPs with selected cardiovascular parameters (including central pulse pressure), clinical conditions and drug treatment profiles in 411 stable ischemic patients with preserved systolic function of the left ventricle. The genotyping of 14 single-nucleotide polymorphisms in 8 genes was carried out either using 5′ exonuclease (TaqMan®) reagents or by restriction analysis. Numerous associations of the investigated polymorphisms with systolic and diastolic blood pressure, maximum left ventricular end diastolic pressure and ejection fraction were observed. While some of the observed effects were found to be age-dependent, associations with clinical conditions (hypertension, diabetes mellitus, angina pectoris) were only observed in women and associations with four groups of drugs (statins, nitrates, calcium channel blockers, anti-aggregation drugs) were only observed in men. The results of this study indicate that the genetic variability of MMPs and TIMPs is an important factor which influences cardiovascular functions and may have important consequences for individual therapy customization in the future.
Recent pre-clinical evidence suggests that the active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump P-glycoprotein. The aim of our study was to evaluate, if the polymoprhisms within ABCB1 gene alter tamoxifen adjuvant treatment efficacy in premenopausal women. Totally 71 premenopausal women with estrogen receptor positive breast cancer indicated for tamoxifen adjuvant treatment were followed retrospectively for median period of 56 months. The gentic polymorphisms of CYP2D6 and ABCB1 were analyzed and potential covariates as tumor grading, staging, age at the diagnosis, comedication, quantitative positivity of ER or PR were also evaluated. Cox proportional-hazards regression model indicated that patients carrying at least one variant allele in ABCB1 rs1045642 had significantly longer time to event survival compared to wild type subjects. Non-significant trend was noted for better treatment outcome of patients carrying at least one variant allele in the SNP rs2032582, while for the CYP2D6 polymorphism poor metabolizer phenotype resulted in worse outcome in comparison to extensive metabolizers subjects with HR of 4.04 (95 % CI 0.31-52.19). Similarly, patients using CYP2D6 inhibitors had non-significantly shorter time-to-event as compared to never users resulting in hazard ratio of 2.06 (95 % CI 0.40-10.63). ABCB1 polymorphisms may affect outcome of tamoxifen adjuvant treatment in premenopausal breast cancer patiens. This factor should be taken into account in addition to the CYP2D6 polymorphism or phenotypic inhibition of CYP2D6 activity., S. Argalácsová, O. Slanař, P. Vítek, P. Tesařová, H. Bakhouche, M. Dražďáková, O. Bartošová, T. Zima, L. Pertuželka., and Obsahuje bibliografii
The availability of the human genome sequence and the recently completed draft sequences of two major mammalian model species, the mouse (Mus musculus) and the rat (Rattus norvegicus), allow researchers to apply novel approaches for gene identification and characterization, using methods of comparative and functional genomics. Recently, a new gene coding for apolipoprotein A-V was identified in the vicinity of APOA-I/C-III/A-IV cluster on human chromosome 11q23 by comparative sequencing method. In a relatively short time, compelling evidence accumulated for the substantial role of APOA-V in lipid metabolism. Studies in knock-out and transgenic mice revealed that its expression pattern correlates negatively with triglyceride levels. This observation was verified in human population studies in variety of ethnic and age groups. Several single nucleotide polymorphisms were described and particular SNP alleles and haplotypes in the APO A-V gene region were shown to be associated with dyslipidemia. The discovery and characterization of the APO A-V demonstrates current possibilities of the integrative approaches in biology, boosted by the available bioinformatic tools., O. Šeda, L. Šedová., and Obsahuje bibliografii