FARMACOGENÉTICA CARDIOVASCULAR

The widely acknowledged variability in drug response is partiality due to differences in genetic background. Pharmacogenetics is a branch within the field of Clinical Pharmacology focused on the study of how genetic differences affect drug responses. Genetic variations (called polymorphisms) may change pharmacokinetic parameters (by altering enzymes involved in drug metabolism), and pharmacodynamic parameters (by altering receptor affinity by agonist and antagonist drugs). Presently, pharmacogenetics has been valued as a potentially useful tool in finding better therapeutics. This review is mostly concerned with cardiovascular pharmacogenetics. Clinical cases will be described and their possible pharmacogenetic implications will be briefly commented on.A variabilidade de resposta à droga entre pacientes é parcialmente devida à composição genética única que cada indivíduos apresenta. O ramo da Farmacologia Clínica que estuda tais variabilidades é chamado de farmacogenética. Variações genéticas (chamadas de polimorfismos) podem modificar tanto parâmetros farmacocinéticos (por alterarem a atividade de enzimas importantes no metabolismo de fármacos) quanto parâmetros farmacodinâmicos (por modificar a afinidade de um receptor pelos agonistas ou antagonistas). Atualmente, a farmacogenética vem sendo valorizada como uma ferramenta útil na busca de terapêuticas melhores. Esta revisão enfoca a farmacogenética de drogas de ação cardiovascular. Especificamente, alguns casos clínicos ilustrativos de doenças cardiovasculares serão apresentados e comentados quanto às suas possíveis bases farmacogenéticas

C>T (rs17035945) polymorphism of TIMP-4 protects against preeclampsia

Made available in DSpace on 2018-12-11T17:24:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-06-01Departamento de Farmacologia, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Botucatu, BrazilDepartamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilDepartamento de Ginecologia e Obstetricia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo (FMRP-USP), Ribeirao Preto, Brazi

Higher levels of circulating TIMP-4 in preeclampsia is strongly associated with clinical parameters and microRNA

Background: Preeclampsia results in maternal and fetal complications and some studies have reported the role of MMPs and TIMPs in its pathophysiology. Therefore, the aim of this study was to compare plasma TIMP-4 levels in preeclampsia and healthy pregnant; and to correlate these levels with clinical parameters and expression of Let7a-5p (3´UTR post-transcriptionally regulation) Methods: TIMP-4 was measured by ELISA and miR-Let7a-5p expression by qPCR. Results: Elevated plasma TIMP-4 levels in preeclampsia compared to healthy pregnant was found 1450 ± 411 vs. 775 ± 210 pg/mL, respectively (p < 0.0001); these levels are correlated positively with serum liver enzymes (ALT, r = 0.84, p = 0.004; and AST, r = 0.51, p = 0.02); and negatively with newborn weight (r = −0.45, p = 0.04) in preeclampsia. Regarding Let7a-5p a negative but not significant correlation was found (r = −0.39, p = 0.06, including both healthy and preeclampsia). Conclusions: Preeclampsia present elevated levels of circulating TIMP-4 compared to healthy pregnant and these levels are correlated with clinical parameters of disease

Circulating Heme Oxygenase-1: Not a Predictor of Preeclampsia but Highly Expressed in Pregnant Women Who Subsequently Develop Severe Preeclampsia

Preeclampsia is the major cause of maternal and fetal deaths worldwide. Circulating biomarker concentrations to predict preeclampsia must be determined. Therefore, the objective was to evaluate heme oxygenase-1 (HO-1) concentration in both plasma and urine samples from pregnant women before the development of preeclampsia and to identify a potential biomarker for preeclampsia development. We performed a case-control study nested in a prospective study cohort at University Hospital of the Ribeirao Preto Medical School, University of São Paulo (HCFMRP-USP), Ribeirao Preto, Brazil. Of 1400 pregnant women evaluated at 20–25 weeks of gestation, 460 delivered in hospitals outside our institution. Of 940 pregnant women who completed the protocol, 30 developed preeclampsia (cases, 14 cases of severe preeclampsia and 16 cases of mild preeclampsia). Healthy pregnant women (controls, n=90) were randomly selected from the remaining 910 participants. HO-1 concentration was evaluated in plasma/urine samples by using a commercial enzyme-linked immunosorbent assay kit. We found similar HO-1 levels in the plasma and urine for case and control groups. In the subgrouped preeclampsia, lower plasma HO-1 levels were found in mild compared with severe preeclampsia. We conclude that plasma HO-1 levels were not altered at 20–25 weeks of gestation before the manifestation of preeclampsia symptoms. Pregnant women who subsequently develop severe preeclampsia show higher expression of HO-1. This may be indicative of important underlying pathophysiologic mechanisms that differentiate between mild and severe preeclampsia and may possibly be related to a higher prooxidative status even before the development of clinical symptoms

Amino Acid Biosignature in Plasma among Ischemic Stroke Subtypes

Ischemic stroke is a neurovascular disorder caused by reduced or blockage of blood flow to the brain, which may permanently affect motor and cognitive abilities. The diagnostic of stroke is performed using imaging technologies, clinical evaluation, and neuropsychological protocols, but no blood test is available yet. In this work, we analyzed amino acid concentrations in blood plasma from poststroke patients in order to identify differences that could characterize the stroke etiology. Plasma concentrations of sixteen amino acids from patients with chronic ischemic stroke (n = 73) and the control group (n = 16) were determined using gas chromatography coupled to mass spectrometry (GC-MS). The concentration data was processed by Partial Least Squares-Discriminant Analysis (PLS-DA) to classify patients with stroke and control. The amino acid analysis generated a first model able to discriminate ischemic stroke patients from control group. Proline was the most important amino acid for classification of the stroke samples in PLS-DA, followed by lysine, phenylalanine, leucine, and glycine, and while higher levels of methionine and alanine were mostly related to the control samples. The second model was able to discriminate the stroke subtypes like atherothrombotic etiology from cardioembolic and lacunar etiologies, with lysine, leucine, and cysteine plasmatic concentrations being the most important metabolites. Our results suggest an amino acid biosignature for patients with chronic stroke in plasma samples, which can be helpful in diagnosis, prognosis, and therapeutics of these patients

T allele of-344C/T polymorphism in aldosterone synthase gene is not associated with resistant hypertension

Resistant hypertension (RH) is the maintenance of elevated blood pressure concurrent with the use of three different anti-hypertensive drugs, one of which is a diuretic. The Renin-Angiotensin-Aldosterone System plays a major role in volume-dependent hypertension. Therefore, its components are interesting targets for genetic association studies. This work focused on the −344 C/T polymorphism in the CYP11b2 gene, which encodes aldosterone synthase. This work evaluates the association between T allele and resistance to anti-hypertensive treatment. Genotyping analysis included 88 subjects with RH, 142 who were responsive to anti-hypertensive treatment and 110 subjects as a control group. Plasmatic concentrations of aldosterone, renin and cortisol, carotid intima-media thickness and carotid-femoral pulse wave velocity were assessed in a smaller subset of hypertensive patients. An association was found between T allele and hypertension (P<0.005), but there was no difference in allele frequencies between both hypertensive groups. There was no difference in plasmatic parameters either, in remodeling indicators between the genotypic groups32159162CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPnão temnão temnão te

Tissue inhibitor of matrix metalloproteinase-1 polymorphism, plasma TIMP-1 levels, and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy

Tissue inhibitor of metalloproteinase (TIMP)-1 is a major endogenous inhibitor of matrix metalloproteinase (MMP)-9, which may affect the responsiveness to therapy in hypertensive disorders of pregnancy. We examined whether TIMP-1 polymorphism (g.-9830T>G, rs2070584) modifies plasma MMP-9 and TIMP-1 levels and the response to antihypertensive therapy in 596 pregnant: 206 patients with preeclampsia (PE), 183 patients with gestational hypertension (GH) and 207 healthy pregnant controls. We also studied the TIMP-3 polymorphism (g.-1296T>C, rs9619311). Plasma MMP-9 and TIMP-1 levels were measured by ELISA. GH patients with the GG genotype for the TIMP-1 polymorphism had lower MMP-9 levels and MMP-9/TIMP-1 ratios than those with the TT genotype. PE patients with the TG genotype had higher TIMP-1 levels. The G allele and the GG genotype were associated with PE and responsiveness to antihypertensive therapy in PE, but not in GH. Our results suggest that the TIMP-1 g.-9830T>G polymorphism not only promotes PE but also decreases the responses to antihypertensive therapy.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP