Nicotine is the primary substance in tobacco causing addiction. In humans the majority (70-80%) of nicotine is inactivated to cotinine in a reaction predominantly catalyzed by CYP2A6 (80-90%), with a minor possible role for CYP2B6. Substantial interindividual variability is observed in the rate of nicotine’s inactivation to cotinine and this variation contributes to differences in smoking behaviors (e.g. cigarette consumption). Twin studies suggest an important genetic contribution to the variability in nicotine metabolism. However in 2004, genetic variation in CYP2A6 and CYP2B6 accounted for only a small portion of the variability suggesting gaps in our knowledge. Our objective was to identify additional genetic and non-genetic sources of variability in CYP2A6 expression/activity, CYP2B6 expression, and nicotine to cotinine metabolism in vivo and/or in vitro. Participants included individuals from different world populations phenotyped for CYP2A6 activity either following oral nicotine administration or using metabolite ratios derived from baseline smoking. Genotyping and sequencing were utilized to identify and characterize multiple new CYP2A6 alleles. In total 17 novel CYP2A6 alleles were identified, many of which were found predominantly among individuals of black African descent and exhibited lower CYP2A6 activity. In addition, human livers were assessed for CYP2A6 and CYP2B6 expression and nicotine to cotinine metabolism. The mechanisms underlying the lower CYP2A6 activity associated with some of the variant CYP2A6 alleles included either a reduction in hepatic CYP2A6 protein expression, an alteration of CYP2A6’s structural property, or a combination of both. DNA methylation was not associated with altered hepatic CYP2A6 expression/activity. Livers from female donors were associated with higher CYP2A6 and CYP2B6 protein expression compared to male livers, while age did not influence the expression of either CYP. Finally, CYP2B6 and its prevalent altered function genetic variant (CYP2B6*6) did not influence nicotine to cotinine metabolism. Identification of factors that contribute to the variability in CYP2A6 and nicotine metabolism is important to improve future association studies between CYP2A6 genotype, nicotine metabolism, and smoking behaviors. In addition, this information could provide the potential to personalize therapy in order to improve the clinical efficacy of nicotine, particularly as a smoking cessation aid.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available in print.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Schizophrenia is a debilitating disorder that occurs the world over. Although antipsychotics are largely effective in treating the positive symptoms of schizophrenia, the outcomes are non-optimal in many patients. As antipsychotic treatment response has been shown to be heritable, it is expected that the implementation of antipsychotic pharmacogenomics should aid in the optimization of antipsychotic treatments, however to date clinically applicable results are limited. Therefore this study utilized exome sequencing in a cohort of well characterized first episode schizophrenia patients to identify the genetic factors contributing to antipsychotic treatment response. The utility of exome sequencing for antipsychotic pharmacogenomic applications in the African context was assessed through examination of the literature and publically available data. Thereafter, a cohort of 104 well characterized South African first episode schizophrenia patients who were treated with flupenthixol decanoate for twelve months was collected. From this cohort, subsets of patients on extreme ends of the treatment response spectrum were identified for exome sequencing. Thereafter a bioinformatics pipeline was used to call and annotate variants. These variants and those that have previously been associated with antipsychotic response, along with a panel of ancestry informative markers, were prioritized for genotyping in the entire cohort of patients. After genotyping of the 393 variants, statistical analyses were performed to identify associations with treatment response outcomes. Examination of the literature revealed a need for exome sequencing in Africa. However, critical analyses of next generation sequencing data demonstrated that complex regions of the genome may not be well suited to these technologies. Thus, it may be necessary to combine exome sequencing with knowledge obtained from past research, as was done in this study to identify the genetic factors contributing to antipsychotic treatment response. Using this strategy, the current study highlighted the potential role that rare variants play in antipsychotic treatment response and additionally detected 11 variants that were significantly associated with antipsychotic treatment response outcomes (P=2.19x10-5). Nine of these variants were predicted to alter the function of the genes in which they occurred; of which eight were novel with regards to antipsychotic treatment response. The remaining two variants have been associated with antipsychotic treatment outcomes in previous GWAS. Examination of the function of the genes in which the variants occurred revealed that the variants associated with (i) positive symptom improvement were involved in the folate metabolism pathway and (ii) negative and general pathological symptoms improvement had potential links to neuronal development and migration. To our knowledge this study is the first to utilize exome sequencing for antipsychotic pharmacogenomic purposes. The ability of this study to identify significant associations, even after correction for multiple testing, has highlighted the importance of combining genomic technologies with well characterized cohorts. The results generated from this study have served both to replicate results from previous antipsychotic pharmacogenetic studies and to identify novel genes and pathways involved in antipsychotic response. These results should aid in improving our understanding of the biological underpinnings of antipsychotic treatment response and may ultimately aid in the optimization of these treatments. / AFRIKAANSE OPSOMMING: Skisofrenie is ‘n siekte wat wêreldwyd voorkom en lei tot erge funksionele inkorting. Alhoewel antipsigotiese medikasie redelik effektief is in die behandeling van die positiewe simptome van skisofrenie, is die funksionele uitkomste in baie pasiënte nie optimaal nie. Die reaksie op antipsigotiese behandeling blyk oorerflik te wees. Die verwagting is dus dat die implementering van antipsigotiese farmakogenomika met die optimalisering van antipsigotiese behandeling sal help. Tot dusver het die resultate van farmakogenomika studies egter beperkte kliniese toepassings opgelewer. Hierdie studie het dus eksoomvolgordebepaling in 'n groep van goed-karakteriseerde eerste-episode skisofrenie pasiënte gebruik om die genetiese faktore wat bydra tot die antipsigotiese behandelings-reaksies te identifiseer. Die gebruik van eksoom-volgordebepaling vir antipsigotiese farmakogenomika in die Afrikakonteks is deur die ondersoek van literatuur en openbaar-beskikbare data geëvalueer. Daarna is 'n groep van 104 goed-gekarakteriseerde Suid-Afrikaanse eerste-episode skisofrenie pasiënte, wat met flupenthixol dekanoaat vir twaalf maande behandel is, versamel. Uit hierdie groep is subgroepe van pasiënte op die teenoorgestelde eindpunte van die behandelings-reaksiespektrum vir eksoom-volgordebepaling geïdentifiseer. Hierna is 'n bioinformatika pyplyn gebruik om variante te identifiseer en te annoteer. Hierdie variante, asook variante wat voorheen met antipsigotiese reaksie geassosieer is, is saam met 'n paneel van afkoms-informatiewe merkers vir genotipering in die hele groep pasiënte geprioritiseer vir genotipering. Na genotipering van die 393 variante, is statistiese analises uitgevoer om assosiasies met behandelings-reaksie uitkomste te identifiseer. ‘n Ondersoek van die literatuur het getoon dat daar 'n behoefte vir eksoomvolgordebepaling in Afrika is. ‘n Kritiese analise van volgende-generasie volgordebepalings data het egter getoon dat komplekse dele van die genoom nie geskik is vir die gebruik van hierdie tegnologie nie. Om die genetiese faktore wat bydra tot suksesvolle antipsigotiese behandeling te identifiseer, mag dit nodig wees om eksoom-volgordebepaling te kombineer met bevindings verkry uit vorige navorsing, soos gedoen in hierdie studie. In die huidige studie het die gebruik van hierdie strategie die potensiële rol van skaars variante in antipsigotiese behandelings-reaksies beklemtoon en ‘n bykomende 11 variante is geïdentifiseer wat beduidend met antipsigotiese behandelingsrespons geassosieer is (P=2.19x10-5). Daar is voorspel dat nege van hierdie variante die funksie van die gene waarin hulle voorkom sal verander en agt van hierdie variante is vir die eerste keer met antipsigotiese behandelingsrespons geassosieer. Die oorblywende twee variante is met antipsigotiese behandelingsrespons in vorige GWAS geassosieer. ‘n Ondersoek na die funksie van die gene waarin die variasies voorgekom het, toon dat die variante wat geassosieer is met (i) verbetering van positiewe simptome ‘n rol speel in folaatmetabolisme, terwyl variante wat geassosieer is met (ii) die verbetering in negatiewe en algemene patologiese simptome potensiële skakels met neuron ontwikkeling en migrasie het. Na ons wete is hierdie die eerste studie wat eksoom-volgordebepaling vir antipsigotiese farmakogenomika doeleindes gebruik. Die vermoë van hierdie studie om beduidende assosiasies te identifiseer, selfs na korreksie vir veelvoudige toetse, onderstreep die belangrikheid van die kombinering van genomiese tegnologie met goed-gekarakteriseerde pasiënte. Die bevindinge van hierdie studie het nie net die resultate van vorige antipsigotiese farmakogenetiese studies bevestig nie, maar ook nuwe gene en variante wat betrokke is in antipsigotiese reaksie geïdentifiseer. Hierdie resultate sal hopelik ons begrip van die onderliggende biologiese faktore wat antipsigotiese behandelingsrespons beïnvloed verbeter en uiteindelik ook met die optimalisering van behandeling help.

Class of 2009 Abstract / This study was partially funded by the Centers for Disease Control Grant No. 1U38GD000070 OBJECTIVES The purpose of this study was to assess the level of pharmacogenetics and pharmacogenomics instruction and of faculty and curriculum development in schools and colleges of pharmacy (here after colleges of pharmacy) in the United States based on the current AACP policy. METHODS: A revised questionnaire based on a previous study by Latif and McKay and 2008 House of Delegates of the American Association of Colleges of Pharmacy (AACP) was sent via email to 90 contacts identified by their respective deans at colleges of pharmacy in the United States. RESULTS: Of the 90 questionnaires sent, seventy-five (83.3% ) usable questionnaires were returned to the investigators. Coverages in the curriculum and its level of importance to the responder were assessed based on the guidelines outlined by AACP. Ninety-one percent of the colleges of pharmacy are currently including pharmacogenetics and pharmacogenomics at the PharmD level, a significant increase (p = 0.0134) from Latif and McKay, with the majority of the instruction as a required didactic course. Less than half (46.7%) of the colleges of pharmacy are planning to increase their course work of pharmacogenetic/pharmacogenomic over the next three years, at the same time as 54.7% have no plans to follow the AACP policy for faculty development. CONCLUSIONS: The genetic basis of disease core competency is being covered and considered important in pharmacogenetic/pharmacogenomic curriculum. Ethical, social and economic implications are also considered an equally important competency in this curriculum; however, it is not being adequately covered. Although pharmacogenetic/pharmacogenomic is currently in the curriculum, the majority of colleges of pharmacy are not adequately prepared to comply with the AACP policy regarding faculty development.

La neurotransmissió dopaminèrgica i serotonèrgica al còrtex preforntal i a les regions del sistema límbic són un dels principals substrats cerebrals de les funcions executives (implicades en l’organització i el control) i la regulació emocinal. Tant la MDMA com el cannabis alteren la funcionalitat d’aquests sistemes de neurotransmissió. Certs polimorfismes funcionals de la catecol-Ometiltransferasa (COMT) i del transportador de serotonina (hSERT) s’han associat a diferències individuals en el funcionament cognitiu. La interacció entre ambdós gens juntament amb factors ambientals poden explicar la major o menor susceptibilitat dels consumidors a els efectes deleteris de les substàncies psicoactives en les arees. L’objectiu és investigar la interacció de diversos polimorfismes relacionats amb els sistemes serotonergic i amb el rendiment d’una població de consumidors de MDMA i cannabis en la realització de diverses tasques neuropsicològiques (memòria i funcions executives pricipalment). / The serotonergic and dopaminegic neurotransmission at the prefrontal-cortex and the areas related to the limbic system, are one of the main substrates for the executive functions (involved in different tasks such as organization and control). Some drugs such as MDMA or cannabis are known to alter these neurotransmission systems. Some functional polymorphisms within the catechol-O-methyltransferase (COMT) and the serotonin transporter gene (hSERT) have been associated to interindividual differences in the cognitive performance. The interaction between both genes and ambient factors can explain to some extent, the different susceptibility of drug users to the deleterious effects of these psychoactive substances. The main objective is to study the relationship between several polymorphisms within the serotonergic and dopaminergic neurotransmission systems and the cognitive performance of a sample of MDMA and cannabis users in several neuropsychological tasks (mainly related to memory and executive functions).

Parvalbumin (PV) and cholecystokinin (CCK) proteins are found in the basolateral amygdala nuclei, particularly in gamma-aminobutyric acid (GABA) interneurons. PV+ neurons were localized to the basolateral amygdala and they expressed the GABA neuron marker glutamic acid decarboxylase (GAD). Here, we used Cre recombinase mouse lines to induce expression of mutant muscarinic inhibitory (hM4D) and excitatory (hM3D) receptors on PV+ or CCK+ neurons. Activation of the mutant receptors with clozapine-n-oxide (CNO) was used to measure how amygdala neural changes affect the acoustic startle reflex (ASR). Excitation of amygdala PV+ neurons potentiated the ASR. Activation of basolateral amygdalar CCK+ neurons potentiated the ASR and caused seizures, possibly by activating glutamate CCK+ neurons. The CCK+ subset of GAD neurons were targeted with a new triple transgenic mouse line (Dlx5-flpe/CCK-Cre/FrePe) to show that most CCK+ neurons were GAD negative. These findings are compared with optogenetic approaches to target specific neuronal populations.

Parvalbumin (PV) and cholecystokinin (CCK) proteins are found in the basolateral amygdala nuclei, particularly in gamma-aminobutyric acid (GABA) interneurons. PV+ neurons were localized to the basolateral amygdala and they expressed the GABA neuron marker glutamic acid decarboxylase (GAD). Here, we used Cre recombinase mouse lines to induce expression of mutant muscarinic inhibitory (hM4D) and excitatory (hM3D) receptors on PV+ or CCK+ neurons. Activation of the mutant receptors with clozapine-n-oxide (CNO) was used to measure how amygdala neural changes affect the acoustic startle reflex (ASR). Excitation of amygdala PV+ neurons potentiated the ASR. Activation of basolateral amygdalar CCK+ neurons potentiated the ASR and caused seizures, possibly by activating glutamate CCK+ neurons. The CCK+ subset of GAD neurons were targeted with a new triple transgenic mouse line (Dlx5-flpe/CCK-Cre/FrePe) to show that most CCK+ neurons were GAD negative. These findings are compared with optogenetic approaches to target specific neuronal populations.

Thesis (MSc (Genetics))--University of Stellenbosch, 2010. / Thesis presented in partial fulfilment of the requirements for the degree of Master of Science (MSc) in Genetics at Stellenbosch University. / ENGLISH ABSTRACT: The prevalence of adverse drug reactions (ADR) and treatment failure in South Africa requires urgent addressing and it is the aim of pharmacogenetics to aid in the alleviation of these ADRs and treatment failures. However, considering the high level of genetic diversity present in African populations, preliminary analysis of the genetic profiles of South African populations is required before pharmacogenetics can be successfully implemented in the South African context. Therefore this study aimed to characterise the gene encoding the drug metabolising enzyme, CYP2C19, in the South African Xhosa population. To identify the common CYP2C19 sequence variation present in the Xhosa population, semiautomated sequence analysis of CYP2C19 was performed on 15 healthy Xhosa individuals. The variation detected was then prioritised through various in silico analyses for further restriction fragment length polymorphism (RFLP) genotyping in an additional 85 healthy Xhosa individuals to confirm the frequencies of the prioritised variants in a larger cohort, while the copy number variation (CNV) present in the entire 100 Xhosa individuals was analysed with the use of duplex real-time PCR. To functionally validate the in silico data obtained for the 5’-upstream variants, dual luciferase reporter assays were utilised. In addition to these analyses, multi-species comparisons were used to highlight regions of high sequence similarity within the 5’-upstream regions, while CpG island analysis was utilised to identify possible CpG islands occurring within and around the CYP2C genes. Sequence analysis of the CYP2C19 gene revealed 30 variants, of which five were novel. Subsequent to RFLP analysis, the frequencies of the allele-defining variants detected in this population, namely CYP2C19*2, CYP2C19*9, CYP2C19*15 and CYP2C19*17 were found to be 0.21, 0.09, 0.09 and 0.10, respectively. Additionally, the novel non-synonymous V374I variant, which was designated CYP2C19*28, was found to occur at a frequency of 0.01. Dual luciferase reporter assays revealed that the construct containing the rs7902257 variant, demonstrated a significant decrease in the fold induction observed when compared to the “wild type” construct (P = 0.0077). This variant was designated CYP2C19*27 and was detected at a frequency of 0.33 in the Xhosa population. In addition to this, multi-species comparisons revealed four highly conserved regions, all of which were present within LINE L1 repetitive elements. Although putative CpG islands were identified in and around the CYP2C genes, no direct correlations could be made between the differences in expression observed between the genes and the presence of the CpG islands. The role of these islands with regards to the epigenetic regulation of these genes therefore remains to be elucidated. To our knowledge, this study provides the most comprehensive data for CYP2C19 in a South African population and shows that the Xhosa population displays a unique genetic profile, which differs from those of other populations, including the Cape Mixed Ancestry population of South Africa. Thus, novel genotyping platforms need to be developed in order to successfully apply pharmacogenetics to the diverse populations residing in South Africa. / AFRIKAANSE OPSOMMING: Die doel van Farmakogenetika is om daadwerklike aandag aan die hoë voorkoms van nadelige geneesmiddel reaksies en mislukte behandelings te skenk en om hierdie voorkoms in Suid-Afrika te verlaag. Die bevolkingsgroepe van Afrika het hoë vlakke van genetiese diversiteit en dus hang die susksesvolle toepassing van Farmakogenetika in Suid-Afrika af van die voorlopige analise van die genetiese profiele van die Suid-Afrikaanse bevolkingsgroepe. Om hierdie rede was die doel van hierdie studie om die geneesmiddel metaboliseerings geen, CYP2C19, in ’n Suid-Afrikaanse Xhosa bevolkingsgroep te karakteriseer. Die CYP2C19 volgorde van 15 Xhosa individue is bepaal om die algemene variasie teenwoordig in die CYP2C19 geen te bevestig. Hierdie variasies is deur verskeie in silico analises geprioritiseer vir verder restriksie fragment lengte polimorfisme (RFLP) genotipering in 85 gesonde Xhosa individue om die frekwensie in ’n groter groep te bevestig, terwyl die kopie aantal variasie teenwoordig in hierdie 100 Xhosas geanaliseer is met Taqman® CNV toetse. Om die in silico data vir die 5’-stroomop variante funksioneel te bevestig, is daar gebruik gemaak van tweedeelige luciferase verklikker toetse. Verder is multi-spesie vergelykings gebruik om 5’-stroomop streke met hoë vlakke van ooreenstemming te identifiseer, terwyl CpG-eiland analise gebruik is om moontlike CpG-eilande in die omgewing van die CYP2C gene te identifiseer. Met behulp van volgorde bepaling van die CYP2C19 geen, is 30 variante geïdentifiseer. Uit hierdie variante was vyf vir die eerste keer met hierdie studie opgespoor. Met die gebruik van RFLP analise, is die alleel definerende variante naamlik CYP2C19*2, CYP2C19*9, CYP2C19*15 and CYP2C19*17, teen ’n frekwensie van 0.21, 0.09, 0.09 en 0.10 in die Xhosa bevolkingsgroep gevind. Verder was die nie-sinonieme variant, V374I, wat vir die eerst keer geïdentifiseer en CYP2C19*28 genoem is, teen ‘n frekwensie van 0.01 gevind. Tweedeelige luciferase verklikker toetse het bewys dat die konstruk met die rs7902257 variant ‘n beduidende afname in induksie in vergelyking met die “wilde tipe” konstruk gewys het (P = 0.0077). Hierdie variant was CYP2C19*27 genoem en was teen ’n frekwensie van 0.33 in die Xhosa bevolking gevind. Die multi-spesie vergelykings het vier gekonserveerde streke geïdentifiseer wat in LINE L1 herhalende elemente gevind is. Alhoewel CpG-eilande in die omgewing van die CYP2C gene gevind is, kon geen direkte korrelasies gemaak word tussen die veranderinge in uitdrukking van die gene en die teenwoordigheid van die CpG-eilande nie. Die rol van hierdie eilande met betrekking tot epigenetiese regulasie van hierdie gene moet dus nog ontrafel word. Tot ons kennis het hierdie projek die mees voledige inligting vir CYP2C19 in ’n Suid-Afrikaanse bevolkingsgroep gegee en het bewys dat die Xhosa bevolkingsgroep ‘n unieke genetiese profiel vertoon, wat van ander bevolkingsgroepe, insluitend die Kaapse Gemenge Herkoms populasie van Suid-Afrika, verskil het. Indien farmokogenetika suksesvol in die diverse bevolkingsgroepe van Suid-Afrika toegepas kan word, moet daar gebruik gemaak word van nuwe genotipering metodes.

Orientador: Heitor Moreno Junior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T13:57:46Z (GMT). No. of bitstreams: 1 Lacchini_Riccardo_M.pdf: 3791091 bytes, checksum: 8936fbea9ef58bfd48f550316c33f122 (MD5) Previous issue date: 2008 / Resumo: Introdução: Hipertensão Refratária se caracteriza por quadro de hipertensão concomitante ao uso de 3 classes diferentes de anti-hipertensivos, sendo, pelo menos um destes, diurético. Existem fatores genéticos que influenciam mecanismos de controle da pressão arterial, podendo ter papel importante na hipertensão refratária. O sistema Renina-Angiotensina-Aldosterona desempenha um papel central na gênese da hipertensão. Isto torna interessante o estudo das influências genéticas sobre sistemas envolvidos com a produção e transporte da aldosterona. Este trabalho apresenta o estudo de um polimorfismo na região promotora do gene CYP11b2 (troca de timina por citosina na posição -344 do gene), que codifica a aldosterona sintase, enzima responsável pelo último passo na síntese de aldosterona pelas glândulas supra-renais. Secundariamente, o trabalho apresenta o estudo de um polimorfismo no exon 26 do gene da p-glicoproteína (troca de citosina por timina na posição 3435 do gene). Esta proteína está envolvida com resistência a diversos medicamentos na terapêutica (o gene é chamado Muliple Drug Resistance-1, MDR-1), e recentemente foi associada a alterações na excreção e captação tecidual de aldosterona. Objetivos: O estudo visa determinar se existe associação entre o alelo T do polimorfismo -344C/T no gene CYP11b2 e a resistência ao tratamento anti-hipertensivo. Secundariamente, é avaliada, de maneira preliminar, a participação do alelo C do gene MDR-1 no fenótipo de hipertensão refratária. Materiais e Métodos: Foram avaliados 340 indivíduos, dos quais 88 eram portadores de HAR que preencheram os requisitos de inclusão no estudo, 142 indivíduos eram hipertensos moderados e responsivos a tratamento farmacológico (HT). Os demais indivíduos (n = 110) constituíram o grupo controle. Foram coletadas amostras de sangue para exames laboratoriais (dentre eles, quantificação de aldosterona, cortisol, renina) e extração de DNA. Foi medida a espessura da íntima média de carótida (EIM) dos pacientes através de ultra-som. Foi estimada a Velocidade de Onda de Pulso carótida-femural (VOP) dos pacientes. O DNA foi extraído pelo método de Salting Out. O polimorfismo do gene CYP11b2 foi genotipado por PCR(Polymerase Chain Reaction) seguido por digestão enzimática com a enzima Hae-III. O polimorfismo do gene MDR-1 foigenotipado através de PCR alelo específico. Resultados: Foi encontrada associação do alelo T do gene CYP11b2 com Hipertensão (p<0,05), porém não houve diferença entre os grupos hipertensos responsivos e hipertensos resistentes. Não houve diferença estatística nas concentrações plasmáticas de aldosterona, cortisol e renina; EIM e VOP nos grupos de alelos C e T. Não foi encontrada relação entre a distribuição alélica do gene MDR-1 e hipertensão tratada ou resistente. Foi detectada associação significativa entre alelo C do gene MDR-1 e pressão arterial diastólica (PAD) aumentada em hipertensos refratários. Conclusões: há associação entre o alelo T do gene CYP11b2 e hipertensão, mas não há associação com resistência farmacológica aos anti-hipertensivos. Não houve influência do alelo T sobre parâmetros clínicos e de remodelamento vascular. O alelo C do gene MDR-1 parece estar associado a uma maior PAD no grupo de hipertensos refratários. / Abstract: Introduction: Resistant hypertension is characterized by elevated blood pressure concurrent with the use of 3 different anti-hypertensive drugs, being one of them a diuretic. There are genetic factors that interfere in the arterial pressure control system and may have a significant role in resistant hypertension. Renin-Angiotensin-Aldosterone System plays a major role in hypertension genesis, therefore the systems that control the production and transport of aldosterone are interesting targets for genetic association studies. This work presents the study of a polymorphism (-344 C/T) in CYP11b2 gene. This gene translates aldosterone synthase, an enzyme responsible for endogenous synthesis of aldosterone on adrenal glands. A secondary study on a polymorphism (3435C/T) in MDR-1 gene was performed. This gene translates p-glicoprotein, an efflux-pump related to several drug resistance phenotypes. Recently it was reported that tissue uptake and excretion of aldosterone is mediated by p-glicoprotein. Objectives: The study aims to evaluate the association between allele T of CYP11b2 and resistance to anti-hypertension treatment. As a second objective it has been performed an initial evaluation of the influence of C allele of MDR-1 on resistant hypertension phenotype. Materials and Methods: In this study, 340 subjects were evaluated: 88 patients presented Refractory Arterial Hypertension (RAH), 142 were responsive to anti-hypertension treatment (RT), and the remaining was the control group (n=110). Blood samples were collected for laboratory examinations (plasmatic aldosterone, cortisol, renin) and DNA extraction. It was examined the carotid intima-media thickness (IMT) using ultra-sound, and carotid-femoral pulse wave velocity (PWV). DNA was extracted using the salting out method. CYP11b2 genotyping was performed through restriction fragment length polymorphism (polymerase chain reaction (PCR) followed by endonuclease digestion). PCR products were digested with Hae III enzyme. MDR-1 genotyping was performed through allele specific PCR. Results: It was found association between allele T of CYP11b2 and hypertension (p<0,005), but no difference has been detected between RT and RAH groups. No statistical difference was detected in plasmatic aldosterone, cortisol and renin concentrations, neither in PWV nor in IMT when compared C and T allele groups. It was found no relationship between alleleC of MDR-1 and hypertension, treated or resistant, although there was a significant association between allele C of this gene and elevated diastolic blood pressure in the RAH group. Conclusions: There is association between allele T of CYP11b2 gene and hypertension, but there is no relationship with pharmacological resistance to antihypertensive treatment. No influence was detected of allele T regarding clinical parameters or remodeling indicators. Allele C of MDR-1 gene seems to be associated with an elevated diastolic blood pressure in resistant hypertensive subjects. / Mestrado / Mestre em Farmacologia