ELIDA PAULA BENQUIQUE OJOPI
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
7 resultados
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Agora exibindo 1 - 7 de 7
- Global pharmacogenomics: Impact of population diversity on the distribution of polymorphisms in the CYP2C cluster among Brazilians(2012) SUAREZ-KURTZ, G.; GENRO, J. P.; MORAES, M. O. de; OJOPI, E. B.; PENA, S. D. J.; PERINI, J. A.; RIBEIRO-DOS-SANTOS, A.; ROMANO-SILVA, M. A.; SANTANA, I.; STRUCHINER, C. J.The impact of biogeographical ancestry, self-reported 'race/color' and geographical origin on the frequency distribution of 10 CYP2C functional polymorphisms (CYP2C8*2, *3, *4, CYP2C9*2, *3, *5, *11, CYP2C19*2, *3 and *17) and their haplotypes was assessed in a representative cohort of the Brazilian population (n = 1034). TaqMan assays were used for allele discrimination at each CYP2C locus investigated. Individual proportions of European, African and Amerindian biogeographical ancestry were estimated using a panel of insertion-deletion polymorphisms. Multinomial log-linear models were applied to infer the statistical association between the CYP2C alleles and haplotypes (response variables), and biogeographical ancestry, self-reported Color and geographical origin (explanatory variables). The results showed that CYP2C19*3, CYP2C9*5 and CYP2C9*11 were rare alleles (<1%), the frequency of other variants ranged from 3.4% (CYP2C8*4) to 17.3% (CYP2C19*17). Two distinct haplotype blocks were identified: block 1 consists of three single nucleotide polymorphisms (SNPs) (CYP2C19*17, CYP2C19*2 and CYP2C9*2) and block 2 of six SNPs (CYP2C9*11, CYP2C9*3, CYP2C9*5, CYP2C8*2, CYP2C8*4 and CYP2C8*3). Diplotype analysis generated 41 haplotypes, of which eight had frequencies greater than 1% and together accounted for 96.4% of the overall genetic diversity. The distribution of CYP2C8 and CYP2C9 (but not CYP2C19) alleles, and of CYP2C haplotypes was significantly associated with self-reported Color and with the individual proportions of European and African genetic ancestry, irrespective of Color self-identification. The individual odds of having alleles CYP2C8*2, CYP2C8*3, CYP2C9*2 and CYP2C9*3, and haplotypes including these alleles, varied continuously as the proportion of European ancestry increased. Collectively, these data strongly suggest that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies of the CYP2C cluster in order to avoid spurious conclusions based on improper matching of study cohorts. This conclusion extends to other polymorphic pharmacogenes among Brazilians, and most likely to other admixed populations of the Americas. The Pharmacogenomics Journal (2012) 12, 267-276; doi: 10.1038/tpj.2010.89; published online 21 December 2010
- Single-nucleotide polymorphisms of GSK3B, GAB2 and SORL1 in late-onset Alzheimer's disease: interactions with the APOE genotype(2013) IZZO, Giselle; FORLENZA, Orestes V.; SANTOS, Bernardo dos; BERTOLUCCI, Paulo H. F.; OJOPI, Elida B.; GATTAZ, Wagner F.; KERR, Daniel ShikanaiIn this study, we investigated the associations between single-nucleotide polymorphisms in GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) and Alzheimer's disease ( AD), both alone and in combination with the APOE*4 allele.
- Association of the UGT1A1-53(TA)(n) polymorphism with L-thyroxine doses required for thyrotropin suppression in patients with differentiated thyroid cancer(2011) VARGENS, Daniela D.; NEVES, Ronaldo R. S.; BULZICO, Daniel A.; OJOPI, Elida B.; MEIRELLES, Ricardo M. R.; PESSOA, Cencita N.; PRADO, Carolina M.; GONCALVES, Pedro A.; LEAL, Vera L. G.; SUAREZ-KURTZ, GuilhermeThere is a considerable interindividual variation in L-thyroxine [ 3,5,3',5'-tetraiodo-l-thyronine (T-4)] dose required for thyrotropin (thyroid-stimulating hormone) suppression in patients with differentiated thyroid cancer. To investigate whether uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)-mediated T-4 glucuronidation in liver affects T-4 dose, we genotyped 101 patients for the common UGT1A1-53(TA)(n) polymorphism and compared T-4 doses among patients having zero (5/6 and 6/6 genotypes), one (6/7 genotype), or two (7/7 and 7/8 genotypes) copies of the low-expression (TA) 7 and (TA) 8 alleles. A significant trend for decreasing T-4 dose with increasing number of copies of (TA)(7) and (TA)(8) (P = 0.037) and significant difference in T-4 dose across the UGT1A1-53(TA)(n) genotypes (P = 0.048) were observed, despite considerable overlap of T-4 doses among different genotypes. These results are consistent with reduced T-4 glucuronidation in patients with low-expression (TA) 7 and (TA) 8 alleles and provide the first evidence for association between UGT1A1-53(TA)(n) and T-4-dose requirement for thyroid-stimulating hormone suppression in a natural clinical setting. Pharmacogenetics and Genomics 21: 341-343 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2011, 21: 341-343
- The Genomic Ancestry of Individuals from Different Geographical Regions of Brazil Is More Uniform Than Expected(2011) PENA, Sergio D. J.; PIETRO, Giuliano Di; FUCHSHUBER-MORAES, Mateus; GENRO, Julia Pasqualini; HUTZ, Mara H.; KEHDY, Fernanda de Souza Gomes; KOHLRAUSCH, Fabiana; MAGNO, Luiz Alexandre Viana; MONTENEGRO, Raquel Carvalho; MORAES, Manoel Odorico; MORAES, Maria Elisabete Amaral de; MORAES, Milene Raiol de; OJOPI, Elida B.; PERINI, Jamila A.; RACCIOPI, Clarice; RIBEIRO-DOS-SANTOS, Andrea Kely Campos; RIOS-SANTOS, Fabricio; ROMANO-SILVA, Marco A.; SORTICA, Vinicius A.; SUAREZ-KURTZ, GuilhermeBased on pre-DNA racial/color methodology, clinical and pharmacological trials have traditionally considered the different geographical regions of Brazil as being very heterogeneous. We wished to ascertain how such diversity of regional color categories correlated with ancestry. Using a panel of 40 validated ancestry-informative insertion-deletion DNA polymorphisms we estimated individually the European, African and Amerindian ancestry components of 934 self-categorized White, Brown or Black Brazilians from the four most populous regions of the Country. We unraveled great ancestral diversity between and within the different regions. Especially, color categories in the northern part of Brazil diverged significantly in their ancestry proportions from their counterparts in the southern part of the Country, indicating that diverse regional semantics were being used in the self-classification as White, Brown or Black. To circumvent these regional subjective differences in color perception, we estimated the general ancestry proportions of each of the four regions in a form independent of color considerations. For that, we multiplied the proportions of a given ancestry in a given color category by the official census information about the proportion of that color category in the specific region, to arrive at a ""total ancestry"" estimate. Once such a calculation was performed, there emerged a much higher level of uniformity than previously expected. In all regions studied, the European ancestry was predominant, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of six million Europeans to Brazil in the 19(th) and 20(th) centuries - a phenomenon described and intended as the ""whitening of Brazil"" -is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. These findings, of both clinical and sociological importance for Brazil, should also be relevant to other countries with ancestrally admixed populations.
- Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients(2011) SANTORO, Ana; FELIPE, Claudia R.; TEDESCO-SILVA, Helio; MEDINA-PESTANA, Jose O.; STRUCHINER, Claudio J.; OJOPI, Elida B.; SUAREZ-KURTZ, GuilhermeAim: Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. The extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C(0)/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation. Materials & methods: Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5(star)3 (rs776746, 6986A>G), (star)6(rs10264272, 14690G>A) and (star) 7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C(0)/dose under a two-step data ana-lysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model. Results: C(0)/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C0/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected. Conclusion: Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5(star)3, (star)6 and (star)7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials. Original submitted 5 April 2011; Revision submitted 4 May 2011
conferenceObject Refractoriness in Schizophrenia is not Associated with Cyp2d6 and Cyp2c19 Genotypes(2012) BILT, Martinus T. van de; PRADO, Carolina M.; OJOPI, Elida P. B.; ZANETTI, Marcus V.; LOCH, Alexandre A.; SOUSA, Rafael A. T.; MACHADO-VIEIRA, Rodrigo; GATTAZ, Wagner F.Background: All genes that encode the CYP450 enzymes are highly polymorphic, leading to different metabolic profiles. While for antidepressants it’s possible to make dose adjustments based on the CYP2D6 and CYP2C19 genotypes, there are currently no evidences validating genotype based adjustments for antipsychotics. Therefore, we aimed to investigate the hypothesis that the prevalence of ultra-rapid metabolizers of neuroleptics would be increased among refractory schizophrenia patients. Methods: 89 schizophrenia patients were enrolled and divided in two groups: 59 refractory patients according to IPAP algorithm (International Psychopharmacology Algorithm Project) and 30 non-refractory patients. Polymorphisms in CYP2D6 and CYP2C19 genes were evaluated by allelic discrimination using the TaqMan® system. The following alleles were investigated: CYP2D6*1, *2, *3, *4, *5, *6, *9, *10, *15, *17, *29, *35, *39, *40, *41 beyond copy number variations and alleles CYP2C19*1, *2, *3 and *17. The phenotypes were classified in extensive metabolizers (EMs), poor metabolizers (PMs), intermediary metabolizers (IMs) and ultra-rapid metabolizers (UMs). Results: The distribution of the CYP2D6 and CYP2C19 phenotypes were as follows: CYP2D6: - Non-refractory: 13.3%PM + IM, 86.6%EM and 0.0% UM - Refractory: 13.5%PM + IM, 86.4%EM and 0.0%UM CYP2C19: - Non-refractory: 16.6%PM + IM, 53.3%EM and 30.0% UM - Refractory: 27.1%PM + IM, 40.6%EM and 32.2%UM Statistical analysis showed no significant difference between the distribution of the CYP2D6 phenotypes (p=0.244) and CYP2C19 predicted phenotypes (p = 0.755) among the two groups. Conclusions: Our findings do not reinforce the inclusion of genotyping of these genes as a tool in the clinical decision making in refractory schizophrenia.- Influence of Genomic Ancestry on the Distribution of SLCO1B1, SLCO1B3 and ABCB1 Gene Polymorphisms among Brazilians(2012) SORTICA, Vinicius de A.; OJOPI, Elida B.; GENRO, Julia P.; CALLEGARI-JACQUES, Sidia; RIBEIRO-DOS-SANTOS, Andrea; MORAES, Manoel Odorico de; ROMANO-SILVA, Marco A.; PENA, Sergio D. J.; SUAREZ-KURTZ, Guilherme; HUTZ, Mara H.The frequency distribution of SNPs and haplotypes in the ABCB1, SLCO1B1 and SLCO1B3 genes varies largely among continental populations. This variation can lead to biases in pharmacogenetic studies conducted in admixed populations such as those from Brazil and other Latin American countries. The aim of this study was to evaluate the influence of self-reported colour, geographical origin and genomic ancestry on distributions of the ABCB1, SLCO1B1 and SLCO1B3 polymorphisms and derived haplotypes in admixed Brazilian populations. A total of 1039 healthy adults from the north, north-east, south-east and south of Brazil were recruited for this investigation. The c.388A>G (rs2306283), c.463C>A (rs11045819) and c.521T>C (rs4149056) SNPs in the SLCO1B1 gene and c.334T>G (rs4149117) and c.699G>A (rs7311358) SNPs in the SLCO1B3 gene were determined by Taqman 5'-nuclease assays. The ABCB1 c.1236C>T (rs1128503), c.2677G>T/A (rs2032582) and c.3435C>T (rs1045642) polymorphisms were genotyped using a previously described single-base extension/termination method. The results showed that genotype and haplotype distributions are highly variable among populations of the same self-reported colour and geographical region. However, genomic ancestry showed that these associations are better explained by a continuous variable. The influence of ancestry on the distribution of alleles and haplotype frequencies was more evident in variants with large differences in allele frequencies between European and African populations. Design and interpretation of pharmacogenetic studies using these transporter genes should include genomic controls to avoid spurious conclusions based on improper matching of study cohorts from Brazilian populations and other highly admixed populations.