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Resumo: Neste trabalho, o objetivo foi estudar a associação de marcadores moleculares dos genes do fator do crescimento semelhante à insulina tipo 1 (IGF1), do hormônio do crescimento (GH) e do fator de transcrição da pituitária (PIT1) com pesos ao nascimento (PN), à desmama (PD), aos 12 (P12) e aos 18 (P18) meses de idade, ganho do nascimento a desmama (GND), idade (IPP) e peso (PPP) ao primeiro parto e perímetro escrotal medido aos 12 (PE12) e 18 (PE18) meses de idade em bovinos da raça Canchim. Análises pelo método de máxima verossimilhança restrita, sob modelo animal indicaram que o gene IGF1 foi responsável por 4±3% da variância fenotípica de PN e o gene GH responsável por 7±6% e 26±13% da variação fenotípica de P12 e PPP, respectivamente. Análises de substituição alélica de IGF1, GH e PIT1 sobre o valor genético (VG) direto e materno (PNmaterno e PDmaterno) das características identificaram que os animais com o alelo "229" de IGF1 teriam VG favoráveis para características reprodutivas e de crescimento. Para GH, o alelo "L" apresentou-se relacionado a maiores VG de P12 e IPP e menores VG de PPP. O alelo "Hinf-" de PIT1 foi associado a menores VG de PN, PDmaterno e IPP e maiores VG de PD e PPP. Concluiu-se que existe um QTL para características de crescimento e reprodutivas segregando junto ao marcador de IGF1. O gene GH foi associado com P12, PPP e IPP, enquanto que o gene PIT1 foi associado ao PD, P12 e PPP. A genotipagem de mais animais, ou a saturação da região desses genes por busca de outros polimorfismos, poderá contribuir para quantificar o exato efeito desses genes sobre as características estudadas / Abstract: Analyses of the association of genetic markers with economic traits in beef cattle have been mainly reported in developed countries. In the Brazilian Canchim breed, studies found association of polymorphism in the insulin-like growth factor 1 (IGF1), growth hormone (GH) and specific pituitary transcriptions (PIT1) genes with growth traits. However, no studies were found that used the variance component approach to estimate the genetic variance due to these genes, or QTLs linked to them, in Canchim cattle.The objective of this study was to evaluate the effects of molecular markers IGF1, GH and PIT1 on the growth and reproductive traits in Canchim cattle. The traits analyzed included: birth weight (BW), weaning weight (WW), average daily gain from birth to weaning (ADG), body weight at 12 (W12) and at 18 months (W18), age at first calving (AFC), body weight at first calving (WFC), scrotal circumference at 12 (SC12) and at 18 months of age (SC18). Proportion of phenotypic variance of these traits that are explained by polymorphisms on the IGF1, GH and PIT1 genes was estimated using the restricted maximum likelihood (REML). In addition the allele substitution effect of these genes on estimated breeding values (EBV) was verified by the least squares method. The polymorphism in the IGF1 explained 4±3% of the BW phenotypic variance, while the polymorphism in GH explained 7±6% e 26±13% of the estimated phenotypic variance for WW and WFC, respectively. There is a QTL for reproductive and growth traits segregating with the marker IGF1. The GH gene was associated with W12, AFC and WFC, while PIT1 was associated with WW, W12 and WFC. Genotyping of more animals or the saturation region of other polymorphisms may help to quantify the exact effect of these genes on these traits / Orientador: Danísio Prado Munari / Coorientador: Claudia Cristina Paro de Paz / Coorientador: Luciana Correia de Almeida Regitano / Banca: Roberto Carvalheiro / Banca: Mônica Corrêa Ledur / Banca: João Ademir de Oliveira / Banca: Sandra Aldair de Queiroz / Doutor

>Magister Scientiae - MSc / Reference single nucleotide polymorphism (refSNP) identifiers are used to earmark SNPs in the human genome. These identifiers are often found in variant call format (VCF) files. RefSNPs can be useful to include as terms submitted to search engines when sourcing biomedical literature. In this thesis, the development of a bioinformatics software package is motivated, planned and implemented as a web application (http://sniphunter.sanbi.ac.za) with an application programming interface (API). The purpose is to allow scientists searching for relevant literature to query a database using refSNP identifiers and potential keywords assigned to scientific literature by the authors. Multiple queries can be simultaneously launched using either the web interface or the API. In addition, a VCF file parser was developed and packaged with the application to allow users to upload, extract and write information from VCF files to a file format that can be interpreted by the novel search engine created during this project. The parsing feature is seamlessly integrated with the web application's user interface, meaning there is no expectation on the user to learn a scripting language. This multi-faceted software system, called SNiPhunter, envisions saving researchers time during life sciences literature procurement, by suggesting articles based on the amount of times a reference SNP identifier has been mentioned in an article. This will allow the user to make a quantitative estimate as to the relevance of an article. A second novel feature is the inclusion of the email address of a correspondence author in the results returned to the user, which promotes communication between scientists. Moreover, links to external functional information are provided to allow researchers to examine annotations associated with their reference SNP identifier of interest. Standard information such as digital object identifiers and publishing dates, that are typically provided by other search engines, are also included in the results returned to the user. / National Research Foundation (NRF) /The South African Research Chairs Initiative (SARChI)

Pisum fulvum Sibth. & Sm. is one of the three species in genus Pisum L., which also includes species Pisum sativum L. and Pisum abyssinicum A.Br. P. fulvum together with subspecies P. sativum subsp. elatius M.Bieb. and P. sativum subsp. humile Boiss. et Noe. belong to the group of wild pea. P. fulvum belongs to secondary gene pool of cultural pea P. sativum L. subsp. sativum. Due to the potential use of P. fulvum as a donor of gene of interest in processes of cultural pea genetic diversity enrichment, it may be considered as an important plant species whose biological characteristics should be assembled within the possibilities. Divergence separating P. fulvum from the rest of the evolutionary lineage of the genus Pisum occured in the period before 1.7 million years +/- 0.4 million years. Currently, its habitats is limited to the eastern part of the territory of Levant where P. fulvum is more abundant plant in its range than other groups of the genus Pisum that occurs sympatric with P. fulvum. The genetic diversity of P. fulvum is characterized in the current thesis by three approaches of molecular biology using DNA sequencing of ITS nuclear region and trnSG chloroplast region, DArT-SeqTM and GenoPea 13.2km SNP. Sequencing ITS region of 149 accessions led to the identification of four ribotypes that were analyzed in biogeographical context. Based on the comparing the analysis of data from genome-wide genotyping DArT-SeqTM and origin of analyzed accessions three groups (south, central and north) which can be considered as intraspecific evolutionary line were identified. In case of analysis of data from GenoPea 13.2K SNP P. fulvum genotype was compared with genotypes of other groups of pea and P. fulvum asociated SNPs were identified. Recent gene flow between some accessions of P. fulvum and accessions of other groups of wild pea was confirmed by analysis of codominant SNP data and by analysis of trnSG sequences.

Nephroblastoma is the most prevalent pediatric kidney tumor, which occurs primarily in younger children with the average age at diagnosis of 42,5 months for girls and 36,5 months for boys. Even though its treatment is currently very succesful and the overall survival rate reaches over 90 %, there are still more things to be discovered and improved. An important role for the right choice of treatment plays not only the histology of tumor, but also the chromosomal changes present at tumor. Some of them (for example 1q gain, simultaneous deletion of 1p and 16q, TP53 deletion) were confirmed as negative prognostic markers because they are associated with an increased risk of relapse or with anaplastic type of nephroblastoma that is included in a high risk group. These changes are therefore used together with the tumor histology for stratification of nephroblastomas. Some of these changes were found in a heterogeneous state (only in a part of the cells) in nephroblastoma, which also complicates the treatment of the patient and which cannot be solved when only one sample is taken from the tumor. In this work we concentrated on the detection of chromosomal changes present in nephroblastomas of 44 patients and their associations with clinical data. We have proved some of the known associations (22q...

Made available in DSpace on 2014-06-11T19:32:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-01Bitstream added on 2014-06-13T20:23:19Z : No. of bitstreams: 1 grossi_da_dr_jabo.pdf: 310388 bytes, checksum: 2b91ab5f611fab0a39c17b2857959958 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Neste trabalho, o objetivo foi estudar a associação de marcadores moleculares dos genes do fator do crescimento semelhante à insulina tipo 1 (IGF1), do hormônio do crescimento (GH) e do fator de transcrição da pituitária (PIT1) com pesos ao nascimento (PN), à desmama (PD), aos 12 (P12) e aos 18 (P18) meses de idade, ganho do nascimento a desmama (GND), idade (IPP) e peso (PPP) ao primeiro parto e perímetro escrotal medido aos 12 (PE12) e 18 (PE18) meses de idade em bovinos da raça Canchim. Análises pelo método de máxima verossimilhança restrita, sob modelo animal indicaram que o gene IGF1 foi responsável por 4±3% da variância fenotípica de PN e o gene GH responsável por 7±6% e 26±13% da variação fenotípica de P12 e PPP, respectivamente. Análises de substituição alélica de IGF1, GH e PIT1 sobre o valor genético (VG) direto e materno (PNmaterno e PDmaterno) das características identificaram que os animais com o alelo “229” de IGF1 teriam VG favoráveis para características reprodutivas e de crescimento. Para GH, o alelo “L” apresentou-se relacionado a maiores VG de P12 e IPP e menores VG de PPP. O alelo “Hinf-” de PIT1 foi associado a menores VG de PN, PDmaterno e IPP e maiores VG de PD e PPP. Concluiu-se que existe um QTL para características de crescimento e reprodutivas segregando junto ao marcador de IGF1. O gene GH foi associado com P12, PPP e IPP, enquanto que o gene PIT1 foi associado ao PD, P12 e PPP. A genotipagem de mais animais, ou a saturação da região desses genes por busca de outros polimorfismos, poderá contribuir para quantificar o exato efeito desses genes sobre as características estudadas / Analyses of the association of genetic markers with economic traits in beef cattle have been mainly reported in developed countries. In the Brazilian Canchim breed, studies found association of polymorphism in the insulin-like growth factor 1 (IGF1), growth hormone (GH) and specific pituitary transcriptions (PIT1) genes with growth traits. However, no studies were found that used the variance component approach to estimate the genetic variance due to these genes, or QTLs linked to them, in Canchim cattle.The objective of this study was to evaluate the effects of molecular markers IGF1, GH and PIT1 on the growth and reproductive traits in Canchim cattle. The traits analyzed included: birth weight (BW), weaning weight (WW), average daily gain from birth to weaning (ADG), body weight at 12 (W12) and at 18 months (W18), age at first calving (AFC), body weight at first calving (WFC), scrotal circumference at 12 (SC12) and at 18 months of age (SC18). Proportion of phenotypic variance of these traits that are explained by polymorphisms on the IGF1, GH and PIT1 genes was estimated using the restricted maximum likelihood (REML). In addition the allele substitution effect of these genes on estimated breeding values (EBV) was verified by the least squares method. The polymorphism in the IGF1 explained 4±3% of the BW phenotypic variance, while the polymorphism in GH explained 7±6% e 26±13% of the estimated phenotypic variance for WW and WFC, respectively. There is a QTL for reproductive and growth traits segregating with the marker IGF1. The GH gene was associated with W12, AFC and WFC, while PIT1 was associated with WW, W12 and WFC. Genotyping of more animals or the saturation region of other polymorphisms may help to quantify the exact effect of these genes on these traits

abstract: Although the Caribbean has been continuously inhabited for the last 7,000 years, European contact in the last 500 years dramatically reshaped the cultural and genetic makeup of island populations. Several recent studies have explored the genetic diversity of Caribbean Latinos and have characterized Native American variation present within their genomes. However, the difficulty of obtaining ancient DNA from pre-contact populations and the underrepresentation of non-Latino Caribbean islanders in current research have prevented a complete understanding of genetic variation over time and space in the Caribbean basin. This dissertation uses two approaches to characterize the role of migration and admixture in the demographic history of Caribbean islanders. First, autosomal variants were genotyped in a sample of 55 Afro-Caribbeans from five islands in the Lesser Antilles: Grenada, St. Kitts, St. Lucia, Trinidad, and St. Vincent. These data were used to characterize genetic structure, ancestry and signatures of selection in these populations. The results demonstrate a complex pattern of admixture since European contact, including a strong signature of sex-biased mating and inputs from at least five continental populations to the autosomal ancestry of Afro-Caribbean peoples. Second, ancient mitochondrial and nuclear DNA were obtained from 60 skeletal remains, dated between A.D. 500–1300, from three archaeological sites in Puerto Rico: Paso del Indio, Punta Candelero and Tibes. The ancient data were used to reassesses existing models for the peopling of Puerto Rico and the Caribbean and to examine the extent of genetic continuity between ancient and modern populations. Project findings support a largely South American origin for Ceramic Age Caribbean populations and identify some genetic continuity between pre and post contact islanders. The above study was aided by development and testing of extraction methods optimized for recovery of ancient DNA from tropical contexts. Overall, project findings characterize how ancient indigenous groups, European colonial regimes, the African Slave Trade and modern labor movements have shaped the genomic diversity of Caribbean islanders. In addition to its anthropological and historical importance, such knowledge is also essential for informing the identification of medically relevant genetic variation in these populations. / Dissertation/Thesis / Zipped file contains Appendices A-K. Supplemental tables, figures, protocols and spreadsheets associated with dissertation. / Doctoral Dissertation Anthropology 2017

Les gènes RUNX1 et CBFB codent pour les sous-unités du core binding factor (CBF), facteur de transcription hétérodimérique essentiel de l’hématopoïèse définitive. La dérégulation du CBF est l'une des anomalies les plus fréquemment rencontrées dans les hémopathies malignes. Puisque la perturbation seule du CBF est insuffisante au développement d’une leucémie aiguë myéloïde (LAM), les LAM impliquant le CBF sont considérées comme des modèles de leucémogénèse multi-étapes, nécessitant la coopération d’anomalies génétiques additionnelles.Dans ce travail, nous nous sommes intéressés aux LAM de type CBF, caractérisées soit par une t(8;21)/fusion RUNX1-RUNX1T1 soit par une inv(16)/fusion CBFB-MYH11, ainsi qu’aux LAM avec mutations germinales de RUNX1 (définissant la thrombopénie familiale avec prédisposition aux leucémies aiguës ou FPD/AML). Afin d’identifier des anomalies additionnelles, nous avons étudié les prélèvements de patients atteints de LAM CBF inclus dans les essais français ELAM02 (0-18 ans) et CBF2006 (18-60 ans) par séquençage à haut débit (n=215) et single nucleotide polymorphism-array (n=198). Les échantillons de 25 individus atteints de FPD/AML (issus de 15 familles), diagnostiqués entre 2005 et 2014, ont également été séquencés au stade thrombopénique et au moment de la transformation en leucémie aiguë.Dans les LAM CBF, les mutations activatrices des voies tyrosines kinases (TK) sont les événements les plus fré-quents quel que soit le sous-type de LAM CBF [t(8;21) ou inv(16)], comme cela a déjà été rapporté dans d’autres études. En revanche, les mutations affectant les gènes du remodelage chromatinien ou du complexe de la cohésine sont identifiées à des fréquences élevées (41% et 18% respectivement) dans les LAM avec t(8;21) tandis qu’elles sont pratiquement absentes dans les LAM avec inv(16). Dans les LAM avec t(8;21), la coexistence de ces mutations avec les mutations de type TK est associée à un pronostic défavorable suggérant une synergie entre ces événements. D'autres événements fréquemment retrouvés incluent les mutations de ZBTB7A et DHX15 dans les LAM avec t(8;21) (20% et 6% respectivement) et les délétions/mutations de FOXP1 dans les LAM avec inv(16) (7%). Enfin, nous avons décrit la perturbation de CCDC26 comme une possible lésion associée à une signalisation aberrante des TK dans les LAM CBF (4,5% des cas).Dans les FPD/AML, l'analyse mutationnelle a révélé l'acquisition d'un deuxième événement impliquant RUNX1 chez tous les patients ayant développé une LAM. Ce deuxième événement correspondait soit à une mutation somatique du second allèle de RUNX1 soit à la duplication de la mutation germinale de RUNX1 (par perte d'hétérozygotie sans anomalie du nombre de copies ou trisomie 21 acquise). En pratique clinique, cela suggère que la présence de deux mutations différentes de RUNX1 ou d'une seule mutation avec un ratio allélique supérieur à 50% chez un patient atteinte de LAM doit alerter sur la possibilité d’un syndrome FPD/AML sous-jacent. / RUNX1 and CBFB encode subunits of the core binding factor (CBF), a heterodimeric transcription factor required for the establishment of definitive hematopoiesis. Deregulation of the CBF is one of the most frequent aberrations in hematological malignancies. Since CBF disruption alone is insufficient to induce acute myeloid leukemia (AML) on its own, AML with CBF involvement is considered as a model of multistep leukemogenesis requiring additional genetic aberrations.Here, we focused on acute myeloid leukemia (AML) with t(8;21)/RUNX1-RUNX1T1 fusion and AML with inv(16)/CBFB-MYH11 fusion, reported together as CBF AML, as well as AML with germline RUNX1 mutation (defining the familial platelet disorder with propensity to develop leukemia or FPD/AML).In order to explore additional genomic aberrations, we performed comprehensive genetic profiling in CBF AML patients enrolled in the French trials ELAM02 (0-18 years) and CBF2006 (18-60 years) using both high-throughput sequencing (n=215) and single nucleotide polymorphism-array (n=198). In addition, we sequenced samples from 25 individuals with FPD/AML (15 pedigrees) diagnosed between 2005 and 2014 at thrombocyto-penic stage and during leukemic progression.In CBF AML, mutations in genes activating tyrosine kinase (TK) signaling were frequent in both subtypes as previously described by others. By contrast, we found mutations in genes encoding chromatin modifiers or members of the cohesin complex with high frequencies in t(8;21) AML (41% and 18% respectively) while they were nearly absent in inv(16) AML. Interestingly, such mutations were associated with a poor prognosis in patients with TK mutations suggesting synergic cooperation between these events. Other events included ZBTB7A and DHX15 mutations in t(8;21) AML (20% and 6% respectively) and FOXP1 deletions or truncating mutations in inv(16) AML (7%). Finally, we described CCDC26 disruption as a possible new lesion associated with aberrant TK signaling in this particular subtype of leukemia (4.5% of CBF AML).In FPD/AML, mutational analysis revealed the acquisition of a second event involving RUNX1 in all patients with AML including somatic mutation of the second allele or duplication of the germline RUNX1 mutation through copy-neutral loss of heterozygosity and trisomy 21. In clinical practice, we suggest that the occurrence of two different RUNX1 mutations or a single RUNX1 mutation with a variant allele frequency higher than 50% in a patient with AML should alert about the possibility of FPD/AML.

As técnicas de marcadores moleculares têm sido aplicadas em estudos populacionais das espécies bovinas, verificação de genealogia e teste de paternidade. Dentre os marcadores moleculares, os microssatélites (MS) são amplamente utilizados, porém, alguns problemas técnicos têm motivado o desenvolvimento de alternativas, como os marcadores do tipo polimorfismo de nucleotídeos único (SNP). Assim, surgiu a necessidade de identificar haplótipos SNP que estão em concordância com cada alelo MS e então os genótipos MS poderiam ser convertidos em genótipos SNP e vice-versa, por meio da imputação do genótipo. O objetivo deste trabalho foi aplicar um método para imputar alelos MS a partir de haplótipos SNP, para verificação de paternidade, utilizando animais da raça Nelore e também identificar um menor conjunto de SNP, com qualidade suficiente para otimizar e diminuir o custo da genotipagem. Foram realizadas genotipagens em SNP e MS para 99 trios de animais da raça Nelore provenientes da EMBRAPA Pecuária Sudeste e foi verificada a existência de alelos nulos pelo programa MICRO-CHECKER. Foram selecionados SNP que estivessem próximos de cada marcador MS e o programa BEAGLE foi usado para identificar a fase de ligação dos genótipos. Posteriormente, foi realizada a técnica de imputação dos MS a partir de haplótipos SNP e foi verificada a paternidade pelo programa CERVUS. A precisão da imputação dos alelos MS foi verificada através do cálculo da concordância entre os alelos MS imputados e relatados. O marcador SPS115 foi removido da análise por evidências de alelos nulos, devido ao excesso de homozigotos observados. O marcador mais informativo foi o TGLA122, cujo conteúdo de informação polimórfica (PIC) foi 0,8. Foram encontrados desvios do equilíbrio de HW (P<0,05) para os locos ETH225 e TGLA57. Um maior conjunto de SNP foi necessário para imputação de alelos MS para o marcador BM1824. As taxas de verificação de parentesco foram de 97,1% para os alelos MS genotipados e 96,3% para os MS imputados. Somente 4% dos 99 filhos não tiveram a paternidade atribuída, quando a simulação foi feita apenas para o pai conhecido e 1% quando pai e mãe eram conhecidos. Esta técnica obteve precisão maior que 96% para a imputação de dados MS e permitiu imputar dados genotípicos multialélicos a partir de bi-alélicos. Os resultados terão um impacto imediato para os pesquisadores e associações de criadores que visam a transição do MS para SNP baseada em verificação de parentesco. / Molecular markers techniques have been applied in bovine population studies, genealogy verification and paternity test. Among the molecular markers, microsatellites (MS) are widely used, however, some technical problems have motivated alternatives development, as markers type single nucleotide polymorphism (SNP). Thus, the need to identify SNP haplotypes which are in agreement with each MS allele and then MS genotypes could be converted into SNP genotypes and vice versa, through genotype imputation. The objective of this study was to apply a method to impute MS alleles from SNP haplotypes to verify paternity, using Nellore and also identify a smaller set of SNP, with enough quality to optimize and reduce genotype cost. SNP genotyping was performed at and for 99 MS trios Nellore from EMBRAPA Cattle Southeast and was checked for null alleles by MICROCHECKER. SNP were selected that were near each MS marker and the program BEAGLE was used to identify genotypes phase. Subsequently, were applied the MS imputation technique from SNP haplotype and paternity was verified by CERVUS. The accuracy of MS alleles imputation was verified by calculating the correlation between MS alleles imputed and reported. The SPS115 marker was removed from the analysis for null alleles evidence due to homozygote excess observed. The most informative marker was TGLA122 with 0.8 PIC. Deviations from equilibrium HW (P<0.05) were found for the loci ETH225 and TGLA57. A larger set of SNP was necessary to impute MS alleles for the marker BM1824. The verification rates of paternity were 97.1% for genotyped MS alleles and 96.3% for MS imputed. Using imputed MS alleles and when only the sire was considered only 4% of the 99 offspring were not assigned paternity and 1% when both parents were known. The technique achieved greater than 96% accuracy for MS imputation data. This research allow to impute multi-allelic genotypes from bi-allelic data. Our results will have an immediate impact for researchers and livestock associations aiming the transition from MS- to SNP-based parentage verification.

Made available in DSpace on 2014-12-17T14:03:34Z (GMT). No. of bitstreams: 1 LeonardoCF_DISSERT_1_30.pdf: 1416070 bytes, checksum: 28ab6b39aaaf4f25a511c52c766f780f (MD5) Previous issue date: 2010-08-02 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Preeclampsia is a multifactorial disease of unknown etiology that features with wide clinical symptoms, ranging from mild preeclampsia to severe forms, as eclampsia and HELLP syndrome. As a complex disease, preeclampsia is also influenced by genetic and environmental factors. Aiming to identify preeclampsia susceptibility genes, we genotyped a total of 22 genetic markers (single nucleotides polymorphisms SNPs) distributed in six candidates genes (ACVR2A, FLT1, ERAP1, ERAP2, LNPEP e CRHBP). By a case-control approach, the genotypic frequencies were compared between normotensive (control group) and preeclamptic women. The case s group was classified according to the disease clinical form in: preeclampsia, eclampsia and HELLP syndrome. As results we found the following genetic association: 1) ACVR2A and preeclampsia; 2) FLT1 and severe preeclampsia; 3) ERAP1 and eclampsia; 4) FLT1 and HELLP syndrome. When stratifying preeclampsia group according to symptoms severity (mild and severe preeclampsia) or according to the time of onset (early and late preeclampsia), it was detected that early preeclampsia is strongly associated to risk preeclampsia, eclampsia and HELLP syndrome have different genetic bases, although FLT1 gene seems to be involved in preeclampsia and HELLP syndrome pathophisiology / A pr?-ecl?mpsia ? uma doen?a multifatorial de etiologia ainda desconhecida que apresenta um amplo espectro quanto ? gravidade dos sintomas, podendo variar da forma mais branda (pr?-ecl?mpsia leve) ?s formas mais severas (ecl?mpsia e s?ndrome HELLP). Atualmente sabe-se que a pr?-ecl?mpsia ? influenciada tanto por fatores ambientais quanto por fatores gen?ticos. Com o prop?sito de identificar genes de suscetibilidade ? doen?a, genotipamos um total de 22 marcadores gen?ticos distribu?dos em seis genes candidatos (ACVR2A, FLT1, ERAP1, ERAP2, LNPEP e CRHBP). Utilizando uma abordagem do tipo casocontrole, comparamos as freq??ncias genot?picas entre mulheres normotensas (controles) e mulheres com pr?-ecl?mpsia (casos). O grupo dos casos foi dividido de acordo a forma cl?nica da doen?a em: pr?-ecl?mpsia, ecl?mpsia e s?ndrome HELLP. Como resultado p?de-se constatar as seguintes associa??es gen?ticas: 1) ACVR2A e pr?-ecl?mpsia; 2) FLT1 e pr?-ecl?mpsia grave; 3) ERAP1 e ecl?mpsia; 4) FLT1 e s?ndrome HELLP. Ao estratificar o grupo da pr?-ecl?mpsia de acordo com a gravidade dos sintomas (pr?-ecl?mpsia leve ou grave) ou de acordo com o tempo de in?cio dos sintomas (pr?-ecl?mpsia precoce ou tardia), comprovamos que o grupo pr?-ecl?mpsia precoce est? fortemente associado aos gen?tipos de risco. Nosso trabalho sugere que a pr?-ecl?mpsia, ecl?mpsia e s?ndrome HELLP possuem bases gen?ticas distintas, embora o gene FLT1 pare?a estar envolvido na fisiopatologia da pr?-ecl?mpsia e s?ndrome HELLP