No description available.

Yes / In psychiatry, the selection of antipsychotics and antidepressants is generally led by a trial-and-error approach. The prescribing of these medications is complicated by sub-optimal efficacy and high rates of adverse drug reactions (ADRs). These both contribute to poor levels of adherence. Pharmacogenetics (PGx) considers how genetic variation can influence an individual’s response to a drug. Pharmacogenetic testing is a tool that could aid clinicians when selecting psychotropic medications, as part of a more personalized approach to prescribing. This may improve the use of and adherence to these medications. Yet to date, the implementation of PGx in mental health environments in the United Kingdom has been slow. This review aims to identify the current barriers and enablers to the implementation of PGx in psychiatry and determine how this can be applied to the uptake of PGx by NHS mental health providers. A systematic searching strategy was developed, and searches were carried out on the PsychInfo, EmBase, and PubMed databases, yielding 11 appropriate papers. Common barriers to the implementation of PGx included cost, concerns over incorporation into current workflow and a lack of knowledge about PGx; whilst frequent enablers included optimism that PGx could lead to precision medicine, reduce ADRs and become a more routine part of psychiatric clinical care. The uptake of PGx in psychiatric care settings in the NHS should consider and overcome these barriers, while looking to capitalize on the enablers identified in this review. / Bradford District Care NHS Foundation Trust in partnership with the University of Bradford; National Institute for Health Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC); National Institute for Health Research Leeds in vitro Diagnostics Co-operative.

Abstract According to recent clinical treatment, doctors give patients medicines based on clinical experience and biochemical data. However, biochemical data simply provides an initial physiology reaction. Although the data is enough for doctors to diagnose diseases, it does not help much for doctors to indicate the most useful medicine. Therefore, doctors will use the first line, cheap or low dose medicine to cure patients by previous clinical experience. It will not only extend the time of treatment but also lower the medical quality. Not to mention the side effects and increases the cost. Consequently, using SNP¡]Single Nucleotide Polymorphism¡^will help doctors to find out different patients¡¦ genotype and forecast the result of medicine. It will control disease efficiently and decrease the medical costs. Methods: This study will be discussed with an accurate test of how to check the genotypes of diabetes mellitus and predict the result of treatment from pharmacogenetic. The method was using PCR (Polymerase Chain Reaction) and RFLP (Restriction Fragment Length Polymorphism) to analyze patients¡¦ different genotype. Besides, this study uses the One-Way ANOVA to interpret the relationship between ABCC8-E16 and type 2 diabetes. In conclusion, the antidiabetic drugs- Sulfonylurea derivatives are suitable for ABCC8-E16 genotype patients. This result can be a reference for doctors to remedy diabetics. It will not only save the cost but also shorten the time of treatment, and it will impact deeply for personalized medicine in the future. type 2 diabetes, Sulfonylurea, SNP, PCR, RFLP, pharmacogenetic, personalized medicine

Οι διαφορετικοί τρόποι ανταπόκρισης στα φάρμακα που παρατηρούνται από άτομο σε άτομο, οι οποίοι βασίζονται στις γενετικές διαφορές μεταξύ διαφόρων πληθυσμών παρουσιάζουν ένα σημαντικό κλινικό πρόβλημα όχι μόνο στην Ελλάδα αλλά και σε άλλες χώρες. Επάνω στο θέμα αυτό έχει αναπτυχθεί ένας καινούργιος κλάδος επιστήμης και υπηρεσιών στην ελληνική αγορά, οι υπηρεσίες γενετικής και φαρμακογενετικής ανάλυσης, οι οποίες μελετούν τις γενετικές διαφορές στα ένζυμα που επηρεάζουν το μεταβολισμό και τη δράση των φαρμάκων στους ασθενείς. Στόχος της εργασίας ήταν η κατανόηση του ρόλου των υπηρεσιών γενετικής και φαρμακογενετικής ανάλυσης στην ελληνική αγορά πραγματοποιώντας μία έρευνα απόψεων ασθενών και του κοινού για την υπηρεσίες γενετικής και φαρμακογενετικής ανάλυσης σε δύο μεγάλες πόλεις (Αθήνα, Πάτρα) και σε μία κωμόπολη (Αίγιο). Για τις ανάγκες της παρούσας εργασίας, ρωτήθηκαν συνολικά 688 άτομα τα οποία χωρίστηκαν σε 3 ηλικιακές ομάδες (<35 ετών, 35-60 ετών και >60 ετών). Το ερωτηματολόγιο αποτελείτο από 9 συνολικά ερωτήσεις με σκοπό να διερευνηθεί (α) το κατά πόσο το ευρύ κοινό είναι ενημερωμένο για το σκοπό των γενετικών και φαρμακογενετικών αναλύσεων, (β) το κατά πόσο το ευρύ κοινό είναι διατεθειμένο να υποβληθεί σε γενετικές/φαρμακογενετικές αναλύσεις, (γ) αν η επιλογή των ατόμων επηρεάζεται από την κάλυψη της ασφάλειας τους, (δ) αν πιστεύουν ότι οι αναλύσεις πρέπει να διενεργούνται κατευθείαν από τους ενδιαφερόμενους ή κατόπιν υπόδειξης από ειδικό. Τα ευρήματα έδειξαν ότι οι περισσότεροι ερωτηθέντες ήταν ενημερωμένοι για τις γενετικές αναλύσεις γνωρίζοντας ότι οι γενετικές αναλύσεις γίνονται με πολύ απλούς τρόπους. Παρατηρήθηκε ότι το μεγαλύτερο ποσοστό των ατόμων ήταν διατεθειμένοι να προβούν σε μια γενετική εξέταση όταν γνώριζαν ότι οι γενετικές αναλύσεις μπορούν να παρέχουν πληροφορίες για την πιθανότητα εμφάνισης μιας κληρονομικής νόσου. Επιπλέον, οι άνθρωποι που ήταν διατεθειμένοι να προβούν στις γενετικές αναλύσεις ήταν περισσότεροι από αυτούς που ήταν διατεθειμένοι να προβούν στις φαρμακογενετικές αναλύσεις. Ωστόσο, οι περισσότεροι πίστευαν ότι οι γενετικές/φαρμακογενετικές αναλύσεις πρέπει να γίνονται από τους ενδιαφερόμενους κατόπιν υπόδειξης από κάποιον ειδικό. Πιο συγκεκριμένα, η μεγάλη πλειοψηφία των ερωτηθέντων πίστευαν ότι οι γενετικές/φαρμακογενετικές αναλύσεις πρέπει να γίνονται κατόπιν υπόδειξης από κάποιον γιατρό και σημαντικά λιγότεροι κατόπιν υπόδειξης από κάποιον φαρμακοποιό. Στις μικρές πόλεις οι πληροφορίες που αφορούν τις γενετικές/φαρμακογενετικές αναλύσεις δεν είναι τόσο διαδεδομένες συγκριτικά με τις μεγάλες πόλεις. Οι περισσότεροι ασθενείς δεν είχαν την ευκαιρία να υποβληθούν σε κάποια γενετική/φαρμακογενετική εξέταση, εφόσον κανείς ποτέ δεν τους παρότρυνε σχετικά. Όμως, αν οι ειδικοί (ειδικά οι γιατροί) μπορούν να παροτρύνουν περισσότερο τους ασθενείς ώστε να υποβληθούν σε τέτοιες εξετάσεις, οι γιατροί θα μπορέσουν να χρησιμοποιούν τα αποτελέσματα των εξετάσεων προκειμένου να καθορίσουν την καλύτερη θεραπευτική επιλογή για τους ασθενείς. Επιπλέον, οι επιλογές των ασθενών επηρεάζονται πολύ από το αν οι αναλύσεις μπορεί να καλύπτονται από ασφαλιστικούς φορείς. Όταν οι δαπάνες των υπηρεσιών καλύπτονται από το δημόσιο ταμείο υγείας ή κάποιους ασφαλιστικούς φορείς, οι ασθενείς θα είναι πιο διατεθειμένοι να υποβληθούν στις εξετάσεις. / Individual difference in drug response is common among patients and it appears to be due to the interactions of genetic factors. Therefore, knowledge about individual genetic variability in drug response is clinically and economically important. Genetic and pharmacogenetic testing which have been developed recently in Greece, study people’s genetic difference in order to predict their response to medicines. Objectives: The purpose of this thesis is to explore patients’ views about genetic and pharmacogenetic testing services and their future development in the Greek market. Methods: 688 questionnaires were distributed to people, originating from 2 major cities (Athens, Patras) and a smaller city (Egio), who were divided into three age groups (<35 years, 35-60 years and >60 years) in Greece. The questionnaires consisted of 9 questions which were designed to explore people’s opinion on (a) how well informed the general public is about the objectives of genetic and pharmacogenetic analysis (b) whether the general public is willing to undertake these tests (c) if their choices will be influenced by reimbursement of testing costs, and (d) if they believe that the tests should be carried out with or without specialists’ (doctor or pharmacist) advice. Results: The views of 688 individuals showed that most responders were aware of genetic tests. They also knew that genetic tests could be easily carried. In addition, the largest percentage of people was willing to order a genetic test when they knew that genetic analysis can inform them on the possibility to develop a hereditary disease. In addition, the number of people who were willing to take genetic tests was more than those who were willing to take pharmacogenetic tests. However, most people believed that genetic / pharmacogenetic tests should only be carried out following the advice of a specialist. In particular, most responders believed that genetic / pharmacogenetic tests should be carried out following the advice of a doctor rather than the advice of a pharmacist. In smaller towns, information about genetic/pharmacogenetic tests is not so much widespread compared to large cities. Conclusion: Most patients have not had the opportunity to take a genetic / pharmacogenetic test as no one has ever suggested them to do so. But if the experts (especially the doctors) could give specific advices to their patients on such tests, the test results could used to determine the best treatment for the patients. Therefore the consequences of side effects or lack of effectiveness of certain drugs could be avoided and drug therapy could be improved. Apart from that, the choices of patients are mostly influenced by their insurance. If the cost of the tests could be reimbursed by some health insurances, patients would be more willing to take the tests.

No description available.

La variabilité de la pharmacocinétique de la névirapine et de l’éfavirenz, deux médicamentsantirétroviraux inhibiteurs non nucléosidiques de la transcriptase inverse du VIH, a été étudiéechez des patients cambodgiens infectés par le VIH par une méthode de pharmacocinétique depopulation. Cent soixante dix patients traités par névirapine faisaient partie de la cohorteESTHER de l’hôpital Calmette de Phnom-Penh et 312 patients co-infectés par le VIH et latuberculose et traités par éfavirenz étaient inclus dans l’essai clinique CAMELIA (ANRS1295–CIPRA KH001) conduit au Cambodge. Les dosages plasmatiques de névirapine et d’éfavirenz ontété réalisés par des méthodes CLHP avec détection UV. Après 18 et 36 mois de traitement, lesconcentrations plasmatiques médianes de la névirapine sont de 5,7 μg/mL. Après 22 et 50semaines de traitement, les concentrations médianes d’éfavirenz sont de 2,7 μg/mL, quel’éfavirenz soit associé (22 semaines) ou non (50 semaines) à la rifampicine. Les clairancesapparentes estimées de la névirapine et de l’éfavirenz sont respectivement de 2,6 L/h et de 7,7L/h. Les variabilités intra et inter individuelles des clairances apparentes sont respectivement de17% et 28% pour la névirapine et 15% et 37% pour l’éfavirenz. Parmi les covariablesdémographiques, biologiques ou génétiques étudiées, seul le polymorphisme génétique duCYP2B6 G516T est significativement associé à la clairance apparente de ces deux médicaments.Ainsi la clairance apparente estimée de la névirapine est de 2,95 L/h, 2,62 L/h et 1,86 L/hrespectivement pour les génotypes CYP2B6 516GG, 516GT, et 516TT. La fréquence de l’allèlemutée T qui code pour une enzyme non fonctionnelle est de 34% dans cette population de 442patients d’Asie du Sud-Est. / HIV-infected patients by population method. 170 patients on nevirapine-based antiretroviraltherapy were from the ESTHER cohort of the Calmette hospital in Phnom-Penh. 312 patients onefavirenz-based therapy were included in the CAMELIA (ANRS1295–CIPRAKH001) clinical trialconducted in Cambodia. Plasma concentrations of nevirapine and efavirenz were measured byHPLC and UV detection. Median plasma concentrations of nevirapine and efavirenz were 5.7μg/mL and 2.7 μg/mL respectively. Apparent plasma clearances of nevirapine and efavirenz were2.6 L/h and 7.7 L/h respectively. Among demographic, clinical, biological or genetic covariates,genetic polymorphism of CYP2B6 G516T was the only one which was shown to affect theclearance of the 2 drugs. Frequency of the T allele was 34% in this population of South-East Asia.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-02-23T12:27:50Z No. of bitstreams: 2 Tese - Rodrigo Bernini de Brito - 2015.pdf: 2201255 bytes, checksum: a184a6bcdb4f9d15e5944a689b43f0e5 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-02-23T12:33:46Z (GMT) No. of bitstreams: 2 Tese - Rodrigo Bernini de Brito - 2015.pdf: 2201255 bytes, checksum: a184a6bcdb4f9d15e5944a689b43f0e5 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-02-23T12:33:46Z (GMT). No. of bitstreams: 2 Tese - Rodrigo Bernini de Brito - 2015.pdf: 2201255 bytes, checksum: a184a6bcdb4f9d15e5944a689b43f0e5 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-08-26 / The aim of pharmacogenetics is to understand the hereditary basis of therapeutic response and side effects of pharmacological agents for each individual. Antipsychotics and antidepressants are effective drugs for schizophrenia and major depressive disorder (MDD) treatment, respectively. Although a number of patients respond satisfactorily to antipsychotics and antidepressants, 20-40% of them present inadequate response, and the treatment with ineffective medication may take weeks of unremitted illness, potential adverse drug reactions and nonadherence to treatment. This study aims to identify polymorphisms in genes that potentially influence the treatment response to clozapine in schizophrenic patients and the treatment with escitalopram in MDD patients. This approach involved the study of CYP1A2 and CYP2C19 genes related to the metabolism of these drugs and which may to affect the efficacy of treatment. It was studied 54 schizophrenic patients taking clozapine and 31 patients with MDD treated with escitalopram, both for long term. The investigated polymorphisms, CYP1A2*1F in schizophrenic patients and CYP2C19*2 and CYP2C19*17 in depressive patients, were analyzed by polymerase chain reaction (PCR), followed by sequencing (CYP1A2*1F) or by restriction fragment length polymorphism (RFLP) (CYP2C19*2 and *17) techniques. The results pointed for the association between CYP1A2*1F polymorphism and super-refractory clozapine treatment and for the association between CYP2C19*17 polymorphism and the decreased response to escitalopram treatment. No association was observed between CYP2C19*2 and the response to escitalopram treatment. These findings suggest that these genetic variants have an important influence on the treatment effectiveness of antipsychotics and antidepressants in psychiatric disorders, as schizophrenia and MDD. The pharmacogenetics may be useful to the psychiatrists helping in the choice of drugs and doses more efficient for each patient, reducing suffering and costs and contributing to improve the quality of life for patients and families. / A farmacogenética busca compreender a base hereditária da variabilidade da resposta e dos efeitos adversos dos agentes farmacológicos entre os indivíduos. Os medicamentos antipsicóticos e antidepressivos são utilizados em tratamentos bastante efetivos para a esquizofrenia e transtorno depressivo maior (TDM), respectivamente. Embora boa parte dos pacientes responda às terapias com antipsicóticos e antidepressivos, 20-40% mostram resposta inadequada, e o custo de cada tentativa de medicação não-efetiva para os pacientes pode levar a semanas de permanência da doença, ocorrência de efeitos adversos potenciais e nãoaderência ao tratamento. Este estudo teve como objetivo identificar polimorfismos genéticos que podem potencialmente influenciar a resposta ao tratamento à clozapina em pacientes esquizofrênicos e ao escitalopram em pacientes com TDM. Essa abordagem envolveu o estudo de genes das enzimas metabolizadoras de fármacos CYP1A2 e CYP2C19, potencialmente envolvidas no metabolismo desses fármacos e que podem afetar a eficácia do tratamento. Foram estudados 54 pacientes esquizofrênicos em uso de clozapina e 31 pacientes com TDM em tratamento com escitalopram, ambos por longo prazo. Os polimorfismos investigados, CYP1A2*1F em pacientes esquizofrênicos e CYP2C19*2 e CYP2C19*17 em pacientes depressivos, foram estudados por métodos baseados na reação em cadeia da polimerase (PCR) seguido por sequenciamento (CYP1A2*1F) ou pela técnica de polimorfismo no comprimento de fragmentos de restrição (RFLP) (CYP2C19*2 e *17). Os resultados encontrados apontam a associação do polimorfismo CYP1A2*1F com a super-refratariedade ao tratamento à clozapina e a associação do polimorfismo CYP2C19*17 com resposta diminuída ao tratamento com escitalopram. Não foi encontrada associação entre o polimorfismo CYP2C19*2 e a resposta ao tratamento ao escitalopram. Os resultados obtidos sugerem que as variantes genéticas CYP1A2*1F e CYP2C19*17 podem desempenhar um papel importante na efetividade do tratamento com antipsicóticos e antidepressivos em transtornos psiquiátricos incapacitantes como a esquizofrenia e o TDM. A farmacogenética pode auxiliar na psiquiatria como ferramenta para a escolha de medicamentos e doses mais adequadas para cada paciente, diminuindo o sofrimento, reduzindo custos e trazendo qualidade de vida a pacientes e familiares.

Sunitinib, an oral vascular endothelial growth factor receptor, is a first-line option for metastatic renal cell carcinoma and widely used in clinical practice. Despite the proven benefit of sunitnib in metastatic renal cell carcinoma, patients may suffer from a variety of adverse events including hypertension, fatigue, hypothyroidism, hand?foot skin reactions, rash, depigmentation, and myelosuppression. Myelosuppression is usually mild, transient and resolves during the two weeks at the end of each cycle where no drug is taken. We present a case of severe and early grade 3 neutropenia and thrombocytopenia occurring two weeks into a six-week cycle. Because of the extreme nature of the toxicity, CYP 3A4 polymorphisms were explored. The patient was found to be heterozygous for CYP 3A4*22, at least partially explaining the early-onset and severity of myelosuppression. This pharmacogenetics information resulted in a rechallenge of dose-reduced sunitinib, which was well tolerated by the patient. The current state of pharmacogenomics concerning sunitinb is also presented, and the need for greater research in this area is highlighted.

Le protocole TICE (Taxol, Ifosfamide, Carboplatine et Etoposide) représente le traitement standard du cancer germinal réfractaire en première ligne ou en rechute de mauvais pronostic. Une étude de phase II a été réalisée consistant en une adaptation de posologie du carboplatine (utilisé à haute dose) basée sur un suivi thérapeutique pharmacologique (TDM) de ses concentrations ultrafiltrables (UF) alors que les pratiques habituelles se limitent à des doses calculées à partir d'une valeur cible de l'aire sous la courbe (AUC) des concentrations UF et la clairance UF prédite du patient. Les analyses pharmacocinétiques effectuées dans le cadre de cette thèse ont permis de démontrer la faisabilité du TDM ainsi que sa performance dans la maîtrise de l'AUC du carboplatine utilisé dans le protocole TICE. Cependant, la réalisation de cette pratique est limitée, dans certains hôpitaux, par les contraintes matérielles et humaines liées à l'obtention des concentrations UF par l'ultrafiltration des prélèvements plasmatiques. Une méthodologie a donc été développée et validée pour permettre la réalisation du TDM à partir des concentrations plasmatiques totales. Par ailleurs, l'étude pharmacocinétique réalisée pour l'étoposide, médicament associé au carboplatine dans la phase d'intensification de ce protocole, indique que le calcul actuel de la dose en fonction de la surface corporelle s'accompagne d'une variabilité interindividuelle limitée de l'exposition et qu'il n'y a pas lieu de pratiquer un TDM pour ce médicament. Enfin, l'implication de différents facteurs génétiques correspondant, d'une part, à la toxicité auditive du carboplatine et, d'autre part, à la pharmacologie de l'étoposide a été aussi évaluée. En conclusion, ces travaux permettront d'améliorer la prise en charge des patients traités par ce protocole à haute dose de carboplatine et étoposide et, au-delà de cette indication thérapeutique, notre connaissance de ces deux médicaments cytotoxiques importants. / The TI-CE protocol ((Taxol, Ifosfamide, Carboplatin and Etoposide) is the standard treatment of germ cell tumor refractory to first-line chemotherapy or relapsed germ cell tumor having unfavorable prognostic features. A phase II study was conducted and consisted in adapting the dose of (high dose) carboplatin using therapeutic drug monitoring (TDM) of unbound concentrations instead of the usual method of dose individualization based on a target area under the curve (AUC) of unbound concentrations and predicted unbound clearance. Pharmacokinetic analyses carried out in the context of this thesis have demonstrated the feasibility of conducting the TDM as well as its performance in terms of controlling the variability of AUC of carboplatin in the TI-CE protocol. However, the use of this practice is limited, in some hospitals, by material and human constraints related to the ultrafiltration of plasma samples to obtain unbound concentrations. A method was developed and validated to enable the use of total plasma concentrations for the TDM instead of unbound concentrations. Furthermore, the pharmacokinetic study of etoposide, used in combination with carboplatin during the dose intensification phase of the protocol, showed that the usual dose calculation method based on body surface area is associated with a low interindividual variability of exposure and that TDM is, therefore, not necessary for this drug. Finally, the role of different genetic factors in the ototoxicity of carboplatin and in the pharmacology of etoposide was also assessed. In conclusion, these analyses help to improve the level of care of patients treated with this protocol of high dose carboplatin and etoposide as well as our current knowledge of these two important cytotoxic drugs.

Orientador: José Eduardo Tanus dos Santos / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T23:52:34Z (GMT). No. of bitstreams: 1 Belo_VanessadeAlmeida_M.pdf: 3576019 bytes, checksum: c9ba06079f310fba660d5bfb890b000a (MD5) Previous issue date: 2011 / Resumo: A obesidade em crianças e adolescentes constitui-se num importante fator de risco para doenças cardiovasculares, em especial, aterosclerose. Esta condição é caracterizada por acúmulo de lipídeos e elementos fibrosos em artérias de grande calibre em que mecanismos inflamatórios e remodelamento vascular estão envolvidos. Neste contexto, a metaloproteinase-9 de matriz extracelular (MMP-9) - endopeptidase capaz de degradar componentes da matriz extracelular - e seu inibidor endógeno preferencial, inibidor tecidual de MMP (TIMP-1) são importantes mediadores deste remodelamento e um equilíbrio entre MMP-9 e TIMP-1 deve existir a fim de manter a integridade do sistema cardiovascular. Ademais, níveis aumentados de MMP-9 são observados em pacientes com doenças cardiovasculares e estudos genéticos têm mostrado ainda que polimorfismos funcionais no gene da MMP-9 têm sido relacionados à presença e severidade de doenças cardiovasculares. Contudo, ainda não se sabe como a associação desses polimorfismos com a obesidade infantil pode afetar as concentrações de MMP-9 no plasma. Logo, os objetivos desse trabalho foram: 1) comparar as concentrações plasmáticas de MMP-9, TIMP-1 e razão MMP-9/TIMP-1 (atividade líquida da MMP-9) entre crianças e adolescentes obesos e controles; 2) comparar as frequências genotípicas e haplotípicas dos polimorfismos C-1562T, -90(CA)14-24 e Q279R da MMP-9 entre obesos e controles e 3) correlacionar as concentrações de MMP-9 aos genótipos e haplótipos da MMP-9. Inicialmente, determinaram-se os níveis de pro-MMP-9 e no plasma, por zimografia, e as concentrações plasmáticas de MMP-9 e TIMP-1 em obesos e controles por ELISA. Nós não encontramos diferenças nas concentrações plasmáticas de MMP-9 e razão MMP-9/TIMP-1 entre obesos e controles. No entanto, nossos resultados revelaram que em obesos houve diminuição de TIMP-1. Em seguida, extraiu-se o DNA dos voluntários e determinaram-se as frequências genotípicas dos polimorfismos C -1562T e (CA)n, por PCR seguida de eletroforese, do polimorfismo Q279R, por PCR em tempo real, e as frequências haplotípicas, pelo programas PHASE. Não houve diferenças nas frequências genotípicas e haplotípicas entre os grupos. Nós avaliamos a relevância de diferentes genótipos e haplótipos nas concentrações plasmáticas de MMP-9. Para os polimorfismos C-1562T e Q279R, nós encontramos que no grupo de obesos, portadores dos genótipos CC apresentaram menores níveis de MMP-9 quando comparados aos portadores dos genótipos CT+TT e aos controles com mesmo genótipo. No grupo de obesos, portadores do genótipo QQ apresentaram menores níveis de MMP-9 quando comparados aos portadores do genótipo RR e aos controles com mesmo genótipo. Para o polimorfismo -90(CA) 14-24 não observamos diferenças nos níveis de MMP-9 entre os grupos genotípicos. Em relação aos haplótipos, no grupo de obesos, portadores do haplótipo H2 apresentaram menores concentrações de MMP-9 e da razão MMP-9/TIMP-1 (atividade líquida de MMP-9) quando comparados aos outros haplótipos e aos controles com mesmo haplótipo. No grupo controle, não observamos influência dos genótipos e haplótipos nas concentrações plasmáticas de MMP-9. Portanto, nossos achados que sugerem que genótipos (CC e QQ) e o haplótipo H2 podem diminuir os níveis circulantes de MMP-9 em crianças e adolescentes obesos, mas não em crianças saudáveis, consequentemente, estes genótipos e haplótipo poderiam oferecer proteção contra doenças cardiovasculares somente em crianças obesas / Abstract: The childhood obesity is important risk factor for cardiovascular diseases, in particular, atherosclerose. This condition is characterized by the accumulation of lipids and fibrous elements in the large arteries in which inflammatory mechanisms and vascular remodeling are involved. In this context, matrix metalloproteinase 9 (MMP-9) - endopeptidade capable of degrading components of extracellular matrix - and its endogenous inhibitor preferential, the tissue inhibitors of MMP (TIMP-1) are important mediators of this remodeling and a critical equilibrium between MMP-9 and TIMP-1 must exist in order to maintain the integrity of cardiovascular system. Moreover, elevated levels of MMP-9 have been reported in patients with cardiovascular diseases, and genetic studies showing that functional polymorphism MMP-9 gene were related to presence and severity of cardiovascular diseases. However, it remains unclear how the association of these polymorphisms with childhood obesity can affect MMP-9 plasma concentrations. Thus, the objectives of this study were: 1) to compare plasma MMP-9, TIMP-1 and MMP-9/TIMP-1(activity) ratio between obese and control groups; 2) to compare the genotype and haplotype frequencies of MMP-9 polymorphisms (C-1562T and (CA)14-24 and Q279R) between obese and control and, 3) correlate the MMP-9 concentrations with MMP-9 genotypes and haplotypes. To achieve our first goal, we determined the plasma pro-MMP-9 levels by zymography, and plasma MMP-9 and TIMP-1 concentrations by ELISA in obese and control. We not found differences in MMP-9 plasma concentratios and MMP-9/TIMP-1 between obese and control. However, our results showed that obese had lower plasma TIMP-1 concentrations than control. Moreover, to achieve our second goal, we firstly extracted DNA from volunteers, and then we determined the genotype frequencies of C-1562T and (CA)14-24 polymorphisms by PCR followed by electrophoresis, of and Q279R polymorphism by real time PCR, and the haplotype frequencies by the programs PHASE. We found similar genotype and allelic distribution for the three polymorphisms when study groups were compared. We evaluated the relevance of different genotypes in plasma MMP-9 concentrations in study groups. To the C-1562T and Q279R polymorphisms, we found that in the obese group, CC genotype carries had lower MMP-9 levels when compared with CT+TT genotype carries and control with the same genotype. In the obese group, QQ genotype carries had lower MMP-9 levels when compared with RR genotype carries and control the same genotype. To the -90(CA)14-24 polymorphism, we did not observe differences in the MMP-9 levels among different genotypic groups. In relation to haplotypes, we found that in the obese group, H2 haplotype carriers had lower MMP-9 levels and MMP-9/TIMP-1 ratio when compared other haplotypes and control with the same haplotype. Therefore, our findings suggest that (CC and QQ) genotypes and H2 haplotype decrease circulating MMP-9 levels in obese but not in healthy children, thus genotypes and haplotype could offer protection against cardiovascular diseases in those children / Mestrado / Farmacologia / Doutor em Farmacologia