Polymorphisms and Haplotypes in Candidate Genes Related to Angiogenesis and Endothelial Dysfunction in Preeclampsia

Valenzuela and colleagues have recently reviewed some polymorphisms in important candidate genes involved in different pathogenic mechanisms related to preeclampsia (PE) and concluded that various studies in different populations have identified maternal polymorphisms associated with PE. However, we would like to contribute to some studies regarding candidate genes related to angiogenesis and endothelial dysfunction in PE performed in the Brazilian population. Specifically, genotypes and haplotypes formed by polymorphisms of VEGF, eNOS and MMP-9, along with an example of the interaction among these genes in the prediction of PE. Our suggestions may provide additional information with clinical relevance to PE susceptibility

Inter-Ethnic Admixture Dynamics in Brazilian Quilombo Remnant Communities

Apesar da intensa mistura étnica na formação da população Brasileira, pequenos grupos isolados ainda podem ser encontrados, principalmente representados pelas tribos indígenas e comunidades remanescentes de quilombo. As comunidades de Barra (BA), São Gonçalo (BA) e Valongo (SC) apresentam diferentes histórias demográficas de formação. Os AIMs (Marcadores Informativos de Ancestralidade) são capazes de revelar essas diferenças pois apresentam grandes diferenciais de freqüência () entre os principais grupos populacionais parentais (africanos, ameríndios, europeus) e, por esta razão, constituem polimorfismos com maior poder discriminante em estimativas de mistura étnica. No presente trabalho, foram testados oito AIMs na análise de três remanescentes de quilombo, comparados a duas amostras de população urbana brasileira. Um destes marcadores, o alelo CYP1A1*2C, foi testado em sete aldeias de quatro tribos da Amazônia Central Brasileira, completando a análise dos outros sete marcadores previamente realizados nestas populações ameríndias. Os objetivos, além da descrição formal de tais populações, incluíam comparar eventuais diferenças entre as comunidades quilombolas e verificar a eficiência relativa destes marcadores em estudos deste tipo. A comparação das freqüências do alelo CYP1A1*2C entre os ameríndios e populações mundiais confirma este alelo como um excelente AIM para diferenciar ameríndios de europeus e africanos, informação importante em estimativas de mistura em populações trihíbridas Brasileiras. As freqüências de oito AIMs (FY-Null, RB, LPL, AT3, Sb19.3, APO, PV92 e CYP1A1*2C) foram então estimadas nas comunidades remanescentes de quilombo de Barra (n=47), São Gonçalo (n=51) e Valongo (n=25) e nas populações urbanas de Jequié (n=47) e Hemosc (Hemocentro de Santa Catarina, n=25) a partir dos fenótipos determinados por PCR e PCRRFLP. As análises estatísticas empregaram programas já descritos (GENEPOP, DISPAN, GDA, STRUCTURE, MVSP e ADMIX 2 e 3). As freqüências alélicas e genotípicas diferenciam todas as comunidades remanescentes e urbanas, fato corroborado pelos valores de FST (p<0,01) par a par entre elas. Outros valores de FST mostram similaridades da comunidade de Barra com africanos e da amostra Hemosc com Europeus, o que é confirmado pelas estimativas do componente africano em Barra (95%) e europeu no Hemosc (83%), como também pelas análises de componente principal. Nestas últimas, o locus FY foi a variável de maior peso (loading) sobre o primeiro componente principal e o PV92 o locus de maior peso sobre o segundo componente principal. Este método demonstrou-se particularmente adequado, pois, em ambas as análises, os dois componentes principais explicaram mais do que 95% da variância total. As estimativas dos componentes africano, europeu e ameríndio em São Gonçalo (68%, 22% e 10%) e JQ (52%, 31% e 17%) mostram que os AIMs geram estimativas de contribuição africana maiores do que as obtidas por STRs autossômicos, YSTRs e marcadores clássicos nas mesmas populações. A estimativa do componente africano em Valongo (68%) foi menor que a obtida a partir dos marcadores clássicos. Isto poderia ser considerado como evidência da maior eficiência destes marcadores na quantificação do componente africano, uma vez que o aumento das estimativas não foi generalizado e, portanto, provavelmente não viciado. Conclui-se que os AIMs seriam mais eficientes para o cálculo da proporção relativa dos diferentes componentes formadores destas populações, pois conduziriam a estimativas mais realistas.In spite of the high degree of inter-ethnic admixture that characterizes the formation of the Brazilian population, small isolated groups, mainly represented by indigenous Amerindian tribes and communities known as quilombo remnants, can still be found. Barra (BA), São Gonçalo (BA) and Valongo (SC) are communities that presented different demographic histories during their formations. The AIMs (Ancestry Informative Markers) are capable of disclosing such differences due to the fact that they present large frequency differentials () between the major ethnic groups that gave origin to the Brazilian population. This provides more reliable information for interethnic admixture estimates. Given that, the present study aimed at establishing the differences regarding inter-ethnic admixture between these three quilombo remnants, which present different demographic histories. The CYP1A1*2C allele frequencies were established in four indigenous tribes from the Brazilian Amazon, which are characterized by low admixture degrees with non-Amerindian people (2-3%), and were compared with frequencies obtained in worldwide populations. This comparison evidenced that such allele is extremely useful for setting Amerindians apart from Europeans and Africans, which is an outstanding feature for estimation of admixture proportions in Brazilian tri-hybrid populations. Allele frequencies of eight AIMs (FY-Null, RB, LPL, AT3, Sb19.3, APO, PV92 and CYP1A1*2C) were obtained in three quilombo remnant communities, Barra (n=47), São Gonçalo (n=51) and Valongo (n=25), and in urban population samples from Jequié (n=47) and Hemosc (n=25), by means of PCR and PCR-RFLP. Statistical analysis were carried out employing the GENEPOP, DISPAN, GDA, STRUCTURE, MVSP and ADMIX 2 and 3 softwares. Allele and genotype frequencies are able to differentiate all quilombo remnant and urban samples, an aspect corroborated by the pair-wise FST (p<0.01) values. Other FST estimates reveal similarities between Barra and Africans and between Hemosc and Europeans, which are supported by the respective African and European admixture estimates in Barra (95%) and Hemosc (83%) and by the Principal Component Analysis. In the latter analysis, the FY locus consisted in the variable with greatest influence (loading) over the first component. On the other hand, the variable PV92 exhibited the highest influence over the second component analysis. This method has proven to be very reliable, given that, in both analyses, the first two principal components explained more than 95% of the total variance. African, European and Amerindian inter-ethnic admixture estimates in São Gonçalo (68%, 22% and 10%) and JQ (52%, 31% and 17%) emphasize the fact that the AIMs provides higher African contribution estimates than the ones obtained by means of autosomal and Y-linked STRs and classical markers in the same populations. African contribution estimated in Valongo (68%) was lower than the one obtained by means of classical markers. Taken together, these estimates may be an evidence of higher effectiveness of this set of markers in quantifying the African component, as long as the increase in African contribution was not generalized and, hence, probably unbiased. In conclusion, the AIMs are more effective in estimating the admixture proportions of the different ethnic components that gave origin to these populations, given that they resulted in more reliable estimates

Inter-Ethnic Admixture Dynamics in Brazilian Quilombo Remnant Communities

Apesar da intensa mistura étnica na formação da população Brasileira, pequenos grupos isolados ainda podem ser encontrados, principalmente representados pelas tribos indígenas e comunidades remanescentes de quilombo. As comunidades de Barra (BA), São Gonçalo (BA) e Valongo (SC) apresentam diferentes histórias demográficas de formação. Os AIMs (Marcadores Informativos de Ancestralidade) são capazes de revelar essas diferenças pois apresentam grandes diferenciais de freqüência () entre os principais grupos populacionais parentais (africanos, ameríndios, europeus) e, por esta razão, constituem polimorfismos com maior poder discriminante em estimativas de mistura étnica. No presente trabalho, foram testados oito AIMs na análise de três remanescentes de quilombo, comparados a duas amostras de população urbana brasileira. Um destes marcadores, o alelo CYP1A1*2C, foi testado em sete aldeias de quatro tribos da Amazônia Central Brasileira, completando a análise dos outros sete marcadores previamente realizados nestas populações ameríndias. Os objetivos, além da descrição formal de tais populações, incluíam comparar eventuais diferenças entre as comunidades quilombolas e verificar a eficiência relativa destes marcadores em estudos deste tipo. A comparação das freqüências do alelo CYP1A1*2C entre os ameríndios e populações mundiais confirma este alelo como um excelente AIM para diferenciar ameríndios de europeus e africanos, informação importante em estimativas de mistura em populações trihíbridas Brasileiras. As freqüências de oito AIMs (FY-Null, RB, LPL, AT3, Sb19.3, APO, PV92 e CYP1A1*2C) foram então estimadas nas comunidades remanescentes de quilombo de Barra (n=47), São Gonçalo (n=51) e Valongo (n=25) e nas populações urbanas de Jequié (n=47) e Hemosc (Hemocentro de Santa Catarina, n=25) a partir dos fenótipos determinados por PCR e PCRRFLP. As análises estatísticas empregaram programas já descritos (GENEPOP, DISPAN, GDA, STRUCTURE, MVSP e ADMIX 2 e 3). As freqüências alélicas e genotípicas diferenciam todas as comunidades remanescentes e urbanas, fato corroborado pelos valores de FST (p<0,01) par a par entre elas. Outros valores de FST mostram similaridades da comunidade de Barra com africanos e da amostra Hemosc com Europeus, o que é confirmado pelas estimativas do componente africano em Barra (95%) e europeu no Hemosc (83%), como também pelas análises de componente principal. Nestas últimas, o locus FY foi a variável de maior peso (loading) sobre o primeiro componente principal e o PV92 o locus de maior peso sobre o segundo componente principal. Este método demonstrou-se particularmente adequado, pois, em ambas as análises, os dois componentes principais explicaram mais do que 95% da variância total. As estimativas dos componentes africano, europeu e ameríndio em São Gonçalo (68%, 22% e 10%) e JQ (52%, 31% e 17%) mostram que os AIMs geram estimativas de contribuição africana maiores do que as obtidas por STRs autossômicos, YSTRs e marcadores clássicos nas mesmas populações. A estimativa do componente africano em Valongo (68%) foi menor que a obtida a partir dos marcadores clássicos. Isto poderia ser considerado como evidência da maior eficiência destes marcadores na quantificação do componente africano, uma vez que o aumento das estimativas não foi generalizado e, portanto, provavelmente não viciado. Conclui-se que os AIMs seriam mais eficientes para o cálculo da proporção relativa dos diferentes componentes formadores destas populações, pois conduziriam a estimativas mais realistas.In spite of the high degree of inter-ethnic admixture that characterizes the formation of the Brazilian population, small isolated groups, mainly represented by indigenous Amerindian tribes and communities known as quilombo remnants, can still be found. Barra (BA), São Gonçalo (BA) and Valongo (SC) are communities that presented different demographic histories during their formations. The AIMs (Ancestry Informative Markers) are capable of disclosing such differences due to the fact that they present large frequency differentials () between the major ethnic groups that gave origin to the Brazilian population. This provides more reliable information for interethnic admixture estimates. Given that, the present study aimed at establishing the differences regarding inter-ethnic admixture between these three quilombo remnants, which present different demographic histories. The CYP1A1*2C allele frequencies were established in four indigenous tribes from the Brazilian Amazon, which are characterized by low admixture degrees with non-Amerindian people (2-3%), and were compared with frequencies obtained in worldwide populations. This comparison evidenced that such allele is extremely useful for setting Amerindians apart from Europeans and Africans, which is an outstanding feature for estimation of admixture proportions in Brazilian tri-hybrid populations. Allele frequencies of eight AIMs (FY-Null, RB, LPL, AT3, Sb19.3, APO, PV92 and CYP1A1*2C) were obtained in three quilombo remnant communities, Barra (n=47), São Gonçalo (n=51) and Valongo (n=25), and in urban population samples from Jequié (n=47) and Hemosc (n=25), by means of PCR and PCR-RFLP. Statistical analysis were carried out employing the GENEPOP, DISPAN, GDA, STRUCTURE, MVSP and ADMIX 2 and 3 softwares. Allele and genotype frequencies are able to differentiate all quilombo remnant and urban samples, an aspect corroborated by the pair-wise FST (p<0.01) values. Other FST estimates reveal similarities between Barra and Africans and between Hemosc and Europeans, which are supported by the respective African and European admixture estimates in Barra (95%) and Hemosc (83%) and by the Principal Component Analysis. In the latter analysis, the FY locus consisted in the variable with greatest influence (loading) over the first component. On the other hand, the variable PV92 exhibited the highest influence over the second component analysis. This method has proven to be very reliable, given that, in both analyses, the first two principal components explained more than 95% of the total variance. African, European and Amerindian inter-ethnic admixture estimates in São Gonçalo (68%, 22% and 10%) and JQ (52%, 31% and 17%) emphasize the fact that the AIMs provides higher African contribution estimates than the ones obtained by means of autosomal and Y-linked STRs and classical markers in the same populations. African contribution estimated in Valongo (68%) was lower than the one obtained by means of classical markers. Taken together, these estimates may be an evidence of higher effectiveness of this set of markers in quantifying the African component, as long as the increase in African contribution was not generalized and, hence, probably unbiased. In conclusion, the AIMs are more effective in estimating the admixture proportions of the different ethnic components that gave origin to these populations, given that they resulted in more reliable estimates

An update on the pharmacogenetics of treating hypertension

Hypertension is a leading cause of cardiovascular mortality, but only one third of patients achieve blood pressure goals despite antihypertensive therapy. Genetic polymorphisms may partially account for the interindividual variability and abnormal response to antihypertensive drugs. Candidate gene and genome-wide approaches have identified common genetic variants associated with response to antihypertensive drugs. However, there is no currently available pharmacogenetic test to guide hypertension treatment in clinical practice. In this review, we aimed to summarize the recent findings on pharmacogenetics of the most commonly used antihypertensive drugs in clinical practice, including diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, beta-blockers and calcium channel blockers. Notably, only a small percentage of the genetic variability on response to antihypertensive drugs has been explained, and the vast majority of the genetic variants associated with antihypertensives efficacy and toxicity remains to be identified. Despite some genetic variants with evidence of association with the variable response related to these most commonly used antihypertensive drug classes, further replication is needed to confirm these associations in different populations. Further studies on epigenetics and regulatory pathways involved in the responsiveness to antihypertensive drugs might provide a deeper understanding of the physiology of hypertension, which may favor the identification of new targets for hypertension treatment and genetic predictors of antihypertensive response.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Ancestry informative markers in Amerindians from Brazilian Amazon

Ancestry informative markers (AIMs) are genetic loci with large frequency differences between the major ethnic groups and are very useful in admixture estimation. However, their frequencies are poorly known within South American indigenous populations, making it difficult to use them in admixture studies with Latin American populations, such as the trihybrid Brazilian population. To minimize this problem, the frequencies of the AIMs FY-null RB2300, LPL, AT3-1/1), Sb19.3, APO, and PV92 were determined via PCR and PCR-RFLP in four tribes from Brazilian Amazon (Tikuna, Kashinawa, Baniwa, and Kanamari), to evaluate their potential for discriminating indigenous populations from Europeans and Africans, as well as discriminating each tribe from the others. Although capable of differentiating tribes, as evidenced by the exact test of population differentiation, a neighbor-joining tree suggests that the AIMs are useless in obtaining reliable reconstructions of the biological relationships and evolutionary history that characterize the villages and tribes studied. The mean allele frequencies from these AIMs were very similar to those observed for North American natives. They discriminated Amerindians from Africans, but not from Europeans. On the other hand, the neighbor-joining dendrogram separated Africans and Europeans from Amerindians with a high statistical support (bootstrap = 0.989). The relatively low diversity (GST = 0.042) among North American natives and Amerindians from Brazilian Amazon agrees with the lack of intra-ethnic variation previously reported for these markers. Despite genetic drift effects, the mean allelic frequencies herein presented could be used as Amerindian parental frequencies in admixture estimates in urban Brazilian populations

Y-STR diversity and ethnic admixture in White and Mulatto Brazilian population samples

We investigated 50 Mulatto and 120 White Brazilians for the Y-chromosome short tandem repeat (Y-STR) markers (DYS19, DYS390, DYS391, DYS392 and DYS393) and found 79 different haplotypes in the White and 35 in the Mulatto sample. Admixture estimates based on allele frequencies showed that the admixture of the white sample was 89% European, 6% African and 5% Amerindian while the Mulatto sample was 93% European and 7% African. Results were consistent with historical records of the directional mating between European males and Amerindian or African females

Y-STR diversity and ethnic admixture in White and Mulatto Brazilian population samples Short Communicaton

Abstract We investigated 50 Mulatto and 120 White Brazilians for the Y-chromosome short tandem repeat (Y-STR) markers (DYS19, DYS390, DYS391, DYS392 and DYS393) and found 79 different haplotypes in the White and 35 in the Mulatto sample. Admixture estimates based on allele frequencies showed that the admixture of the white sample was 89% European, 6% African and 5% Amerindian while the Mulatto sample was 93% European and 7% African. Results were consistent with historical records of the directional mating between European males and Amerindian or African females. The Brazilian population is a result of interethnic crosses of Europeans, Africans and Amerindians, and is one of the most heterogeneous populations in the world. When the first European colonizers arrived (1500 AD), 1-5 million Amerindians already lived in the region that now is known as Brazil (Salzano and Callegari-Jacques, 1988). Before 1820, European colonization was almost exclusively composed of Portuguese while between 1820 and 1975 the great majority of immigrants were from Portugal and Italy, followed by a small number by people from Spain, Germany, Syria and Japan . Between the 16 th and 19th centuries approximately 3.5 million Africans were brought as slaves to Brazil, coming mainly from West, West-Central and Southeast Africa Although the classification of races is wrong from genetic standpoint We investigated 170 healthy, unrelated, individuals seeking paternity investigation at the Ribeirão Preto University Hospital, in the city of Ribeirão Preto, São Paulo state, Southeastern Brazil. The race of the individuals in the sample was determined based on their biomedical records, 120 individuals being White and 50 Mulatto, from Ribeirão Preto and the surrounding towns. We assessed the Y-STR loci DYS19, DYS390, DYS391, DYS392 and DYS393 Allele and haplotype frequencies were estimated by the gene counting method and gene and haplotype diversities calculated using the ARLEQUIN software version 2.00

Epistasis among eNOS, MMP-9 and VEGF maternal genotypes in hypertensive disorders of pregnancy

Polymorphisms of the endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) genes were shown to be associated with hypertensive disorders of pregnancy. However, epistasis is suggested to be an important component of the genetic susceptibility to preeclampsia (PE). The aim of this study was to characterize the interactions among these genes in PE and gestational hypertension (GH). Seven clinically relevant polymorphisms of eNOS (T-786C, rs2070744, a variable number of tandem repeats in intron 4 and Glu298Asp, rs1799983), MMP-9 (C-1562T, rs3918242 and -90(CA)(13-25), rs2234681) and VEGF (C-2578A, rs699947 and G-634C, rs2010963) were genotyped by TaqMan allelic discrimination assays or PCR and fragment separation by electrophoresis in 122 patients with PE, 107 patients with GH and a control group of 102 normotensive pregnant (NP) women. A robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. Although no significant genotype combinations were observed for the comparison between the GH and NP groups (P&gt;0.05), the combination of MMP-9-1562CC with VEGF-634GG was more frequent in NP women than in women with PE (P&lt;0.05). Moreover, the combination of MMP-9-1562CC with VEGF-634CC or MMP-9-1562CT with VEGF-634CC or-634GG was more frequent in women with PE than in NP women (P&lt;0.05). These results are obscured when single polymorphisms in these genes are considered and suggest that specific genotype combinations of MMP-9 and VEGF contribute to PE susceptibility. Hypertension Research (2012) 35, 917-921; doi:10.1038/hr.2012.60; published online 10 May 2012Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP-Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilFundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazi