Produção Nacional
Revisado por pares
Letter to the Editor: Combined CYP2C9 , VKORC1 and CYP4F2 frequencies among Amerindians, Mozambicans and Brazilians
2011; Future Medicine; Volume: 12; Issue: 6 Linguagem: Inglês
10.2217/pgs.11.35
ISSN1744-8042
AutoresDaniela D. Vargens, Albertino Damasceno, Maria Luiza Petzl‐Erler, Guilherme Suarez‐Kurtz,
Tópico(s)Inflammatory mediators and NSAID effects
ResumoPharmacogenomicsVol. 12, No. 6 News & ViewsFree AccessLetter to the Editor: Combined CYP2C9, VKORC1 and CYP4F2 frequencies among Amerindians, Mozambicans and BraziliansDaniela D Vargens, Albertino Damasceno, Maria-Luiza Petzl-Erler & Guilherme Suarez-KurtzDaniela D VargensDivisão de Farmacologia, Instituto Nacional do Câncer, Rio de Janeiro, RJ20231-050, Brazil, Albertino DamascenoServiço de Cardiologia, Faculdade de Medicina, Universidade Eduardo Mondlane, Maputo, Mozambique, Maria-Luiza Petzl-ErlerLaboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brazil & Guilherme Suarez-Kurtz† Author for correspondencePublished Online:21 Jun 2011https://doi.org/10.2217/pgs.11.35AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail The pharmacogenomics of warfarin has been investigated extensively in recent years, in an effort to explain the interindividual variability in the clinical response to this widely used anticoagulant. These studies have consistently demonstrated that polymorphisms in CYP2C9 and VKORC1 modulate the warfarin dose requirement in various populations. In addition, a polymorphism in CYP4F2 has been implicated in warfarin dose/response in patients of European descent. Several warfarin dosing algorithms incorporating polymorphisms in VKORC1, CYP2C9 and, in some cases, CYP4F2 as covariates have been described [1]. The predictive power of these algorithms varies markedly across populations, in part owing to interethnic differences in the frequency of the relevant pharmacogenetic polymorphisms [2,3]. In a recent issue of Pharmacogenomics, Scott et al. explored this notion by comparing the combined frequency of variant VKORC1, CYP2C9 and CYP4F2 alleles among African–Americans, Asian, Caucasian, Hispanic and Ashkenazi Jewish populations [4]. We extended this approach to populations that are consistently under-represented in pharmacogenomic databases, namely Amerindians (Native Americans) and sub-Saharan Africans. In addition, we present data for an admixed Brazilian cohort, with African, European and Amerindian ancestral roots.Amerindians were represented by 90 healthy adult Guarani (Guarani-Kaiowá, Guarani-Ñandeva and Guarani-M'byá), who were contacted in indigenous reservation areas located in the states of Mato Grosso do Sul and Paraná, in Brazil's center-west and south regions, respectively, for a study of population genetics [5], approved by the Brazilian National Ethics Committee. The sub-Saharan African cohort consisted of 103 adult Mozambicans (34 healthy subjects and 69 cardiovascular patients under warfarin therapy), recruited in Maputo, Mozambique, as part of a study approved by the Ethics Committee of the Universidade Eduardo Mondlane, Maputo, Mozambique. Adult Brazilians, self-identified as white (n = 196), brown ('pardo', in Portuguese, n = 118) and black (n = 76), according to the Brazilian Census classification [101], were recruited in Rio de Janeiro, Brazil's southeast region. These individuals were under stable warfarin therapy and have been described in previous studies by our group [6,7].The allele frequency of the CYP2C9, CYP4F2 and VKORC1 variants genotyped in Mozambicans, Guarani and Brazilians are shown in Table 1. Allele discrimination at each locus was performed on a Fast 7500 Real-Time System (Applied Biosystems, Foster City, CA) using validated Taqman® assays purchased from Applied Biosystems. The three cohorts differed significantly (p < 0.0001, Table 1) with respect to the frequency distribution of the CYP2C9, CYP4F2 and VKORC1 variants. Pairwise comparisons revealed highly significant (p < 0.0001) differences between Brazilians versus Guarani or Mozambicans in the frequency of CYP2C9, CYP4F2 and VKORC1 polymorphisms. Guarani and Mozambicans differed significantly with respect to VKORC1 (p < 0.0001) and CYP2C9 (p = 0.0004), whereas a nonsignificant (p = 0.07), albeit large (100%), difference was observed in relation to CYP4F2 rs2108622.Pairwise comparisons between Guarani, Mozambicans or Brazilians and each of the groups studied by Scott et al.[4] revealed significant differences in 39 out of the 45 comparisons (Table 2). We will not comment on every pairwise comparison, but would like to highlight three distinct observations: first, Mozambicans and African–Americans differed significantly in the frequency of CYP2C9 and VKORC1 polymorphisms. This may be explained, in part, by European admixture in African–Americans [8], but could also reflect the genetic diversity of sub-Saharan African populations [9]. Second, the significant differences in frequency of CYP2C9 and VKORC1 polymorphisms between Brazilians and Hispanics highlight the inappropriateness, from a pharmacogenomics perspective, of lumping the diverse Latin American populations into a single racial/ethnic category, namely Hispanic or Latino. Third, Guarani differed significantly from Asians in the frequency of CYP2C9 and CYP4F2 variants, despite Asia being the likely origin of the first migrants into the American continent, 25,000–15,000 years ago [10,11]. Random genetic drift and/or founder effects, that is, a consequence of a small number of migrants colonizing new lands, may explain the observed divergence in CYP2C9 and CYP4F2 allele frequency. Pairwise comparison of Guarani and the Asian cohort studied by Scott et al. did not reveal significant differences in frequency of VKORC1 rs9923231 [4], which conflicts with our previous findings [12]. We ascribe this discrepancy to the relatively low frequency (0.67) of VKORC1 rs9923231 in the Asians genotyped by Scott et al.[4] compared with other Asian cohorts (0.90) [2,3].In the context of warfarin dosing algorithms, it is noteworthy that VKORC1 rs9923231 allele A, CYP2C9*2 and *3 are rare or absent in Mozambicans. Considering the major contribution of these three SNPs to the performance of most warfarin algorithms, it might be anticipated that such algorithms will perform poorly in Mozambicans, as they do in other cohorts of African descent [13–15]. The inclusion of additional CYP2C9 (e.g., CYP2C9*5, *8, *11 and rs7089580) and VKORC1 (rs61162043) variants has been demonstrated to improve the predictive ability of warfarin dosing algorithms for African–Americans [15,16]. Furthermore, polymorphisms in other genes (e.g., CALU rs339097) are associated with higher warfarin dose requirements, in African–Americans [17]. It would be important to verify whether these findings apply to other populations of African descent. To the best of our knowledge, warfarin algorithms have not been validated in Amerindians. However, the frequency of VKORC1 3673A in Guarani (0.59) approaches the range (0.6–0.7), which provides the highest estimates of the percentage variance in warfarin dose explained by VKORC1 across populations [2]. This favorable feature is opposed by the low combined frequency (0.05) of CYP2C9 variants among Guarani. Future studies are required to assess the performance of warfarin algorithms in Guarani and other Amerindian groups. The Brazilian cohort has been previously used for development and validation of warfarin dosing algorithms. These algorithms included VKORC1 3673G>A and CYP2C9*2, *3, *5 and *11 as pharmacogenetic covariates, and explained 51–60% of the interindividual variance in warfarin dose requirement. Addition of the CYP2C9*8 allele had marginal effect on the algorithms' predictive power [Suarez-Kurtz G, Unpublished data], which is not unexpected considering the low frequency of this allele in southeast Brazilians (0.03, Table 1). We have previously reported that prospective CYP4F2 genotyping for inclusion in warfarin algorithms is not justified in this Brazilian cohort [18].In conclusion, we reported the frequency of CYP2C9, CYP4F2 and VKORC1 polymorphisms in an Amerindian (Guarani), a sub-Saharan African (Mozambican) and a highly admixed European/Amerindian/African cohort (southeast Brazilians) population, and examined the consequences of the distinct allele profiles on the predictive power of warfarin dosing algorithms.Table 1. CYP2C9, CYP4F2 and VKORC1 allele frequencies.Gene/SNPsdbSNPAllele frequency (95% CI) Guarani (n = 180)Mozambican (n = 206)Brazilian† (n = 780)CYP2C9*2rs17998530.011 (0–0.06)00.124 (0.09–0.16)*3rs105791000.010 (0–0.05)0.056 (0.04–0.08)*5rs2837168600.019 (0.02–0.07)0.003 (0–0.02)*6rs9332131000*8rs79001940.044 (0.01–0.11)0.146 (0.08–0.23)0.033 (0.02–0.06)*11rs2837168500.024 (0.01–0.05)0.006 (0–0.01)Combined 0.055 (0.02–0.12)0.199 (0.13–0.29)0.217 (0.18–0.26)CYP4F2*3rs21086220.044 (0.01–0.11)0.087 (0.04–0.16)0.26‡ (0.22–0.31)VKORC13673G>Ars99232310.586 (0.48–0.69)§0.035 (0.01–0.10)0.347¶ (0.30–0.40)n: Number of chromosomes.†Data for Brazilians are expressed as 'weighted' frequency, calculated by multiplying the allele frequency for white, brown and black individuals by the corresponding percentage of each 'race/color' in the population of Brazil´s southeast region in the 2009 Brazilian Census[101].‡Data taken from[18].§Data taken from[12].¶Data taken from[6].Table 2. Allele frequency comparison of CYP2C9, CYP4F2 and VKORC1 polymorphisms across populations†.Study groupsGenesAfrican–AmericanAsianCaucasianHispanicAshkenazi JewishGuaraniCYP2C9‡0.050.001<0.0001<0.0001<0.0001 CYP4F20.005<0.0001<0.0001<0.0001<0.0001 VKORC1<0.00010.09§0.0050.00040.004MozambicanCYP2C9‡<0.0001<0.00010.0001<0.0001<0.0001 CYP4F20.30§<0.0001<0.00010.0001<0.0001 VKORC10.001<0.0001<0.0001<0.0001<0.0001BrazilianCYP2C9‡<0.00010.00040.09§0.009<0.0002 CYP4F2<0.00020.22§0.020.40§0.002 VKORC1<0.0001<0.00010.11§0.02<0.0001†Data expressed as χ2 p-values for pairwise comparisons between the study populations and those reported by Scott et al. [4].‡Refers to the frequency distribution of variant alleles CYP2C9*2, *3, *5, *8 and *11.§Nonsignificant differences.AcknowledgementsThe collaboration of Jamila A Perini and Natalia Soares in the genotyping of polymorphisms is acknowledged.DisclaimerThis work is the opinion of the authors and does not represent the views of Future Medicine or its employees.Financial & competing interests disclosureThe research was supported by grants from Financiadora de Estudos e Projetos (FINEP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (Faperj). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Ethical conduct of researchThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.Bibliography1 Jonas DE, McLeod HL: Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol. Sci.30(4),375–386 (2009).Crossref, Medline, CAS, Google Scholar2 Limdi NA, Wadelius M, Cavallari L et al.: Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood115(18),3827–3834 (2010).Crossref, Medline, CAS, Google Scholar3 Ross KA, Bigham AW, Edwards M et al.: Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. J. Hum. Genet.55(9),582–589 (2010).Crossref, Medline, CAS, Google Scholar4 Scott SA, Khasawneh R, Peter I et al.: Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics11(6),781–791 (2010).Link, CAS, Google Scholar5 Tsuneto LT, Probst CM, Hutz MH et al.: HLA class II diversity in seven Amerindian populations. Clues about the origins of the Aché. Tissue Antigens62(6),512–526 (2003).Crossref, Medline, CAS, Google Scholar6 Perini JA, Struchiner CJ, Silva-Assunção E et al.: Pharmacogenetics of warfarin: development of a dosing algorithm for Brazilian patients. Clin. Pharmacol. Ther.84(6),722–728 (2008).Crossref, Medline, CAS, Google Scholar7 Suarez-Kurtz G, Perini JA, Silva-Assunção E et al.: Relative contribution of VKORC1, CYP2C9, and INR response to warfarin stable dose. Blood113(17),4125–4126 (2009).Crossref, Medline, CAS, Google Scholar8 Parra EJ: Admixture in North America. In: Pharmacogenomics in Admixed Populations. Suarez-Kurtz G (Ed.). Landes Bioscience, TX, USA, 28–46 (2007).Google Scholar9 Tishkoff AS, Reed FA, Friedlaender FR et al.: The Genetic structure and history of Africans and African Americans. Science324(5930),1035–1044 (2009).Crossref, Medline, CAS, Google Scholar10 Cavalli-Sforza LL, Menozzi P, Piazza A: The History and geography of Human Genes. Princeton University Press, NJ, USA (1994).Google Scholar11 Salzano FM, Bortolini MC: The Evolution and Genetics of Latin American Populations. Cambridge University Press, Cambridge, UK (2002).Google Scholar12 Perini JA, Petzl-Erler ML, Tsuneto LT, Suarez-Kurtz G: VKORC1 polymorphisms in Amerindian populations of Brazil. Pharmacogenomics9(11),1623–1629 (2008).Link, CAS, Google Scholar13 Gage BF, Eby C, Johnson JA et al.: Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin. Pharmacol. Ther.84(3),326–331 (2008).Crossref, Medline, CAS, Google Scholar14 International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB et al.: Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med.360(8),753–764 (2009).Crossref, Medline, CAS, Google Scholar15 Cavallari LH, Langaee TY, Momary KM et al.: Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin. Pharmacol. Ther.87(4),459–464 (2010).Crossref, Medline, CAS, Google Scholar16 Perera MA, Gamazon E, Cavallari LH et al.: The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin. Pharmacol. Ther.89(3),408–415 (2011).Crossref, Medline, CAS, Google Scholar17 Voora D, Koboldt DC, King CR et al.: A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clin. Pharmacol. Ther.87(4),445–451 (2010).Crossref, Medline, CAS, Google Scholar18 Perini JA, Struchiner CJ, Silva-Assunção E, Suarez-Kurtz G: Impact of CYP4F2 rs2108622 on the stable warfarin dose in an admixed patient cohort. Clin. Pharmacol. Ther.87(4),417–420 (2010).Crossref, Medline, CAS, Google Scholar101 Instituto Brasileiro de Geografia e Estatística (IBGE), responsible for the Brazilian Census www.ibge.gov.brGoogle ScholarFiguresReferencesRelatedDetailsCited ByPharmacogenomics research and clinical implementation in Brazil24 January 2019 | Basic & Clinical Pharmacology & Toxicology, Vol. 124, No. 5The Genetics of Warfarin Dose–Response Variability in Africans: An Expert Perspective on Past, Present, and FutureOMICS: A Journal of Integrative Biology, Vol. 23, No. 3VKORC1-1639A allele influences warfarin maintenance dosage among Blacks receiving warfarin anticoagulation: a retrospective cohort studyFatima Donia Mili, Tenecia Allen, Paula Weinstein Wadell, W Craig Hooper, Christine De Staercke, Christopher J Bean, Cathy Lally, Harland Austin & Nanette K Wenger8 December 2017 | Future Cardiology, Vol. 14, No. 1Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population9 December 2016 | BMC Research Notes, Vol. 9, No. 1Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes23 November 2015 | Expert Opinion on Drug Metabolism & Toxicology, Vol. 11, No. 12Preemptive Genotyping of CYP2C8 and CYP2C9 Allelic Variants Involved in NSAIDs Metabolism for Sickle Cell Disease Pain Management2 February 2015 | Clinical and Translational Science, Vol. 8, No. 4Effect of clinical factors and gene polymorphism of CYP2C19*2, *17 and CYP4F2*3 on early stent thrombosisNora Kupstyte, Remigijus Zaliunas, Vacis Tatarunas, Vilius Skipskis, Diana Zaliaduonyte-Peksiene, Ingrida Grabauskyte, Dovile Dovidaitiene, Karolis Bumblauskas, Olivija Gustiene & Vaiva Lesauskaite25 February 2015 | Pharmacogenomics, Vol. 16, No. 3CYP2C9 Allelic Variants and Frequencies in a Pediatric Sickle Cell Disease Cohort: Implications for NSAIDs Pharmacotherapy29 May 2014 | Clinical and Translational Science, Vol. 7, No. 5Frequency of selected single nucleotide polymorphisms influencing the warfarin pharmacogenetics in Slovak population12 May 2014 | European Journal of Haematology, Vol. 93, No. 4Pharmacogenomic implications of population admixture: Brazil as a model caseGuilherme Suarez-Kurtz, Daniela Polessa Paula & Claudio J Struchiner21 January 2014 | Pharmacogenomics, Vol. 15, No. 2Pharmacogenomics of warfarin in populations of African descent10 January 2013 | British Journal of Clinical Pharmacology, Vol. 75, No. 2Personalized medicine: is it a pharmacogenetic mirage?5 September 2012 | British Journal of Clinical Pharmacology, Vol. 74, No. 4Distribution of CYP2C Polymorphisms in an Amerindian Population of Brazil4 November 2011 | Basic & Clinical Pharmacology & Toxicology, Vol. 110, No. 4 Vol. 12, No. 6 Follow us on social media for the latest updates Metrics History Published online 21 June 2011 Published in print June 2011 Information© Future Medicine LtdAcknowledgementsThe collaboration of Jamila A Perini and Natalia Soares in the genotyping of polymorphisms is acknowledged.DisclaimerThis work is the opinion of the authors and does not represent the views of Future Medicine or its employees.Financial & competing interests disclosureThe research was supported by grants from Financiadora de Estudos e Projetos (FINEP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (Faperj). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Ethical conduct of researchThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.PDF download
Referência(s)