FARMACOGENÉTICA DE FÁRMACOS HIPOLIPEMIANTES

Although, the pharmacological treatment for cholesterol reduction has been an advance in the cardiovascular and atherosclerosis treatment, the benefits are still limited due to interindividual variability in the response to these drugs. Disease severity, treatment adhesion, physiological conditions, biological conditions as well as the patient genetic profile could be cited as important factors for the evaluation of interindividual variability. In this context, three large groups of genes could be investigated: a) Genes that codify proteins involved in metabolism and/or transport of drugs, influencing the pharmacokinetics of these compounds. b) Genes that codify proteins involved in the mechanism of action and/or in the metabolic pathway where of drug action (pharmacodynamics). c) Genes that codify proteins involved in the direct development of the disease or in intermediate phenotypes. In this revision we discussed pharmacogenetic studies of the main lipid lowering drugs, and the expectations in relation to pharmacogenetics in order to help our prediction capacity in relation to treatment efficacy as well as the possibility to reduce adverse effects of these drugs. As soon as new studies would be performed and that most of the genetic variability associated with drug action would be disclosed, the great challenge would be the application of this knowledge in practical medicine.Embora o tratamento farmacoterapêutico para redução dos níveis de colesterol tenha sido um dos grandes avanços no tratamento de doenças cardiovasculares e aterosclerose, os benefícios são ainda limitados devido a variabilidade interindividual na resposta a esses medicamentos. Entre os fatores importantes para a avaliação da variabilidade interindividual pode-se citar a severidade da doença, adesão ao tratamento, condições fisiológicas, condições biológicas e o perfil genético do paciente. Neste contexto, três grandes grupos de genes podem ser analisados: a) Genes que codificam proteínas envolvidas na metabolização e/ou transporte dos fármacos, influenciando a farmacocinética dos compostos. b) Genes que codificam proteínas envolvidas no mecanismo de ação e/ou nas rotas metabólicas em que o fármaco age (farmacodinâmica). c) Genes que codificam proteínas envolvidas no desenvolvimento direto da doença ou de fenótipos intermediários. Nessa revisão discutimos os estudos farmacogenéticos dos principais fármacos hipolipemiantes e a expectativa em relação a fármacogenética de auxiliar em nossa capacidade de predição em relação à eficácia do tratamento e a possibilidade de redução dos efeitos adversos a esses medicamentos. Na medida que novos estudos forem efetuados e que a grande parte da variabilidade genética envolvidas nas diferenças interindividuais na ação de fármacos for elucidada, o grande desafio será a aplicação desses conhecimentos na prática médica

Alterações metabólicas associadas à terapia anti-retroviral em pacientes HIV-positivos

OBJECTIVE: To evaluate metabolic changes associated with highly active antiretroviral therapy (HAART) in HIV-positive patients, and to identify risk factors associated. METHODS: Retrospective study that included 110 HIV-positive patients who where on HAART in the city of Porto Alegre (Southern Brazil) between January 2003 and March 2004. Data on demographic variables, cigarette smoking, diabetes mellitus, cholesterol and triglyceride levels, stage of HIV infection, antiretroviral therapy and HCV coinfection were collected. General linear models procedure for repeated measures was used to test the interaction between HAART and HCV coinfection or protease inhibitor treatment. RESULTS: Total cholesterol, triglycerides, and glucose levels significantly increased after receiving HAART (pOBJETIVO: Evaluar las alteraciones metabólicas asociadas a la terapia anti-retroviral potente en pacientes HIV-positivos e identificar factores de riesgo asociados. MÉTODOS: Estudio retrospectivo con 110 pacientes HIV-positivos que estaban en terapia anti-retroviral potente (HAART) en la ciudad de Porto Alegre (Sur de Brasil), entre enero de 2003 y marzo de 2004. Los datos colectados incluyen variables demográficas, tabaquismo, diabetes mellitas, niveles de colesterol y triglicéridos, fase de la infección viral, terapia anti-retroviral y co-infección con hepatitis C. El análisis multivariado para medidas repetidas (General Linear Model procedure for Repeated Measures) fue utilizada para analizar la interacción entre el efecto de uso de HAART y el uso de inhibidores de proteasa o co-infección por hepatitis C. RESULTADOS: Fueron observados aumentos significativos en los niveles de colesterol total, triglicéridos y glucosa posterior al tratamiento con HAART (pOBJETIVO: Avaliar as alterações metabólicas associadas à terapia anti-retroviral potente em pacientes HIV-positivos e identificar fatores de risco associados. MÉTODOS: Estudo retrospectivo com 110 pacientes HIV-positivos que estavam sob terapia anti-retroviral potente (HAART) na cidade de Porto Alegre (RS), entre janeiro de 2003 e março de 2004. Os dados coletados incluem variáveis demográficas, tabagismo, diabetes mellitus, níveis de colesterol e triglicerídeos, estágio da infecção viral, terapia anti-retroviral e co-infecção com hepatite C. A análise multivariada para medidas repetidas (General Linear Model procedure for Repeated Measures) foi utilizada para testar a interação entre o efeito do uso de HAART e o uso de inibidores de protease ou co-infecção por hepatite C. RESULTADOS: Foram observados aumentos significativos nos níveis de colesterol total, triglicerídeos e glicose após o tratamento com HAART (

Blood groups in Native Americans : a look beyond ABO and Rh

The study presents comparisons between blood group frequencies beyond ABO and Rh blood systems in Native American populations and previously published data from Brazilian blood donors. The frequencies of Diego (c.2561C>T, rs2285644), Kell (c.578C>T, rs8176058), Duffy (c.125A>G, rs12075, c.1−67T>C, rs2814778) and Kidd (c.838A>G, rs1058396) variants in Kaingang (n=72) and Guarani (n=234) populations from Brazil (1990–2000) were obtained and compared with data from these populations sampled during the 1960s and with individuals of different Brazilian regions. Data showed high frequencies of DI*01 and FY*01 alleles: 11.8% and 57.6% in Kaingang and 6.8% and 75.7% in Guarani groups, respectively. The main results indicated: (1) reduction in genetic distance over time of Kaingang and Guarani in relation to other Brazilian populations is suggestive of ongoing admixture; (2) significant differences in some frequencies of blood group markers (especially Diego, Kidd and Duffy) in relation to Native Americans and individuals from different geographical regions of Brazil. Our study shows that the frequency of red blood cell polymorphisms in two Native American groups is very different from that of blood donors, when we evaluated blood groups different from ABO and Rh systems, suggesting that a better ethnic characterization of blood unit receptors is necessary

Physical fitness attenuates the genetic predisposition to obesity in children and adolescents

Obesity is an important risk factor associated with non-communicable cardiometabolic diseases. Previous studies have indicated that children and adolescents with a predisposed genetic risk for obesity could benefit from an active lifestyle, but there are no studies investigating whether physical fitness moderates the association of genetics and obesity. The aim of this study was to verify the moderating role of physical fitness in the relationship between genetic risk score (GRS) and body mass index (BMI) in children and adolescents. This cross-sectional study was carried out with 1471 children and adolescents, aged between 6 and 17 years from Santa Cruz do Sul, Brazil. Weight and height were assessed to determine BMI. Physical fitness components (cardiorespiratory fitness [CRF], lower limb strength [LLS], upper limb strength, and abdominal strength) were evaluated. The GRS was based on previously associated obesity single-nucleotide polymorphism rs9939609 (FTO), rs6548238 (TMEM18), and rs16835198 (FNDC5). Moderation analyses were tested using linear regression models, and the interactions were represented by physical fitness components X GRS (categorical variable). All analyses were adjusted for skin color/ethnicity, sex, and sexual maturation. Significant interactions for CRF (P = 0.041), LLS (P = 0.041), and abdominal strength (P = 0.046) X 5 and 6 risk alleles with BMI were found only in adolescents. In addition, there was evidence that fitness components attenuated the high genetic predisposition to high BMI. Physical fitness components are moderators in the relationship between GRS and BMI in adolescents. These findings highlight the need for interventions targeting to improve this aspect, which is an important health indicator in all ages

Proteína C Reativa, Função Endotelial e Influência Genética: Associação com a Obesidade

Obesity is a multifactor chronic disease and its incidence has been increasing over the years and is being considered a public health problem. It is characterized by a chronic state of low grade inflammation, in which the C-reactive protein levels are usually increased. This inflammatory process can change the endothelial function in these individuals, since elevated levels of C-reactive protein are related to a low production of nitric oxide, which is responsible for the endothelium vasodilation. Several studies have demonstrated the influence of polymorphisms in the genes of C-reactive protein and of the endothelial nitric oxide synthesis enzyme in obese and healthy individuals. Thus this literature review aims at discussing the relationship between obesity and C-reactive protein levels and endothelial function, as well as to elucidate the association of genetic factors. Scientific articles from the databases PubMed, Science Direct and Scielo were consulted, using the following keywords and combinations of them: C-reactive protein, function/endothelial dysfunction, polymorphism and obesity. Thus, we concluded that obese individuals have elevated levels of C-reactive protein as a result of excess of body fat and this implies a reduction in nitric oxide synthesis. All these factors can be influenced by polymorphisms in regulatory genes of the production of these proteins.A obesidade é uma doença crônica e multifatorial, que vem aumentando sua incidência ao longo dos anos e está sendo considerada um problema de saúde pública. É caracterizada por um estado crônico de baixo grau de inflamação, no qual os níveis de proteína C reativa geralmente estão aumentados. Esse processo inflamatório pode alterar a função endotelial nesses indivíduos, uma vez que os níveis elevados de proteína C reativa estão relacionados a uma baixa produção de óxido nítrico, o qual é responsável pela vasodilatação do endotélio. Vários estudos têm demonstrado a influência de polimorfismos nos genes da proteína C reativa e da enzima óxido nítrico sintase endotelial em indivíduos obesos e saudáveis. Dessa forma, esta revisão de literatura tem como objetivo discutir a relação da obesidade com níveis de PCR e função endotelial, bem como elucidar a associação de fatores genéticos. Foram consultados artigos científicos dos bancos de dados PubMed, Science Direct e Scielo, utilizando os seguintes descritores e combinações entre eles: proteína C reativa, função/ disfunção endotelial, polimorfismo e obesidade e seus respectivos em inglês. Com isso, concluímos que indivíduos obesos apresentam elevados níveis de proteína C reativa, em decorrência do excesso de gordura corporal, e isso implica uma redução na síntese de óxido nítrico. Todos esses fatores podem ser influenciados por polimorfismos nos genes reguladores da produção dessas proteínas

Biochemical profile, eating habits, and telomere length among Brazilian children and adolescents

Objectives: Lifestyle, obesity, and eating habits are emerging as determinants for the instability of telomeres. The increase in childhood and adolescent obesity and the association of biochemical profiles and dietary components with telomere length (TL) makes it an important issue in nutritional research. The aim of the present study was to investigate TL and its association with ethnic background, adiposity, clinical and biochemical parameters, and dietary patterns among Brazilian children and adolescents. Methods: A cross-sectional study encompassing 981 children and adolescents between 7 and 17 y of age was performed. Dietary intake habits, anthropometry, and clinical data were collected. TL analysis was performed by quantitative polymerase chain reaction. Results: Children presented significantly longer TL than adolescents (P = 0.046). Participants who self-declared as black, mulatto, or brown (P < 0.001) also showed longer TL than those who were white. Regarding biochemical parameters, individuals with altered glucose levels had shorter TL than normoglycemic participants in the total sample (P = 0.014). Such difference remained statistically significant in adolescents (P = 0.019). Participants who reported eating fruits and vegetables regularly had longer TL than those who did not (P < 0.001). Conclusion: The results suggested that both biochemical parameters and the intake of antioxidant-rich food, such as fruits and vegetables, are associated with the stability of telomere biology among young Brazilians

Estudo da influência da variabilidade em genes de apolipoproteínas sobre níveis lipídicos e parâmetros de massa e gordura corporal na população de Porto Alegre

Apolipoproteínas constituem a parte proteica das lipoproteínas e de uma maneira geral desempenham papéis como proporcionar estabilidade estrutural, solubilizar lipídeos altamente hidrofóbicos, servir como ligantes a receptores ou agir como co-fatores para enzimas envolvidas no metabolismo. Diversos estudos têm mostrado que a variabilidade dos genes que codificam estas proteínas podem influenciar os níveis lipídicos em diversas populações. A variabilidade da apo A-IV também foi associada com variáveis antropométricas. Nesta investigação foram analisados 8 RFLPs nos genes das apolipoproteínas C-I (HpaI), C-II (AvaII), C-III (SacI, FokI e MspI) e A-IV (XbaI, HinfI e PvuII). A amostra foi composta por 391 indivíduos caucasóides de Porto Alegre (RS) e dados sobre hábitos de vida, dosagens lipídicas e medidas antropométricas foram obtidas para cada indivíduo. Os fragmentos de interesse de cada gene foram amplificados por PCR e os genótipos foram identificados por eletroforese em géis de agarose ou poliacrilamida corados com brometo de etídio.Apolipoproteins constitute the protein fraction of lipoproteins. In general, these proteins provide structural stability, solubilize hydrophobic lipids, function as receptor ligands, and act as cofactors to metabolic enzymes. Investigations providing evidences about the influence of the genetic variability of these proteins on lipid levels in different populations have been published. The apo A-IV genetic variability is also associated with anthopomentric variables. In the present investigation, we have analysed 8 RFLPs in the apolipoproteins C-I (HpaI), C-II (AvaII), C-III (SacI, FokI, and MspI), and A-IV genes (XbaI, HinfII, and PvuII). The sample was composed by 391 unrelated Caucasian individuals from Porto Alegre (RS). Data about lifestyle, lipid levels and anthropometric measures were obtained for each individual. The specific sequences of each gene were amplified by PCR and genotypes were identified after electrophoresis of the digested DNA fragments on agarose or polyacrylamide gels stained with ethidium bromide and visualized under UV light