BACKGROUND: The study of genetic variants alone is not enough to explain a complex disease like cancer. Alterations in DNA methylation patterns have been associated with different types of tumor. In order to detect markers of susceptibility for the development of cutaneous melanoma and breast cancer in the Uruguayan population, we integrated genetic and epigenetic information of patients and controls. METHODS: We performed two case-control studies that included 49 individuals with sporadic cutaneous melanoma and 73 unaffected controls, and 179 women with sporadic breast cancer and 209 women controls. We determined the level of global leukocyte DNA methylation using relative quantification of 5mdC by HPLC, and we compared methylation levels between cases and controls with nonparametric statistical tests. Since the Uruguayan population is admixed and both melanoma and breast cancer have very high incidences in Uruguay compared to other populations, we examined whether individual ancestry influences global leucocyte DNA methylation status. We carried out a correlation analysis between the percentage of African, European and Native American individual ancestries, determined using 59 ancestry informative markers, and global DNA methylation in all participants. RESULTS: We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001). Additionally, we found a negative correlation between African ancestry and global DNA methylation in cancer patients (p <0.005). CONCLUSIONS: These results support the potential use of global DNA methylation as a biomarker for cancer risk. In addition, our findings suggest that the ancestral genome structure generated by the admixture process influences DNA methylation patterns, and underscore the importance of considering genetic ancestry as a modifying factor in epigenetic association studies in admixed populations such as Latino ones.

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Doenças cardiovasculares (DCVs) são a principal causa de morbidade e mortalidade no mundo e a etnia do indivíduo tem uma importante influência no diagnóstico e tratamento dessas doenças. No entanto, as bases das disparidades étnicas ainda não estão completamente esclarecidas. O estudo de uma população com alta miscigenação genética, fornece potenciais maneiras de compreender a influência genética na determinação de fenótipos de doenças complexas, como as cardiovasculares, em raízes ancestrais comuns. O presente estudo teve como objetivo principal associar etnia auto referida e ancestralidade genética em indivíduos de uma coorte brasileira com fatores de risco para doenças cardiovasculares. Identificamos associação entre etnia auto referida e hipertensão arterial, acidente vascular cerebral (AVC) e hipercolesterolemia. Analisando a hipercolesterolemia com mais detalhes, encontramos associação de etnia com níveis séricos de triglicerídeos (TG), lipoproteína de alta densidade (HDL-c) e índice TG/HDL-c. Essas associações foram fortemente dependentes de confundidores socioeconômicos, mas variações existem na força e direção de cada padrão. No entanto, observamos que o efeito de etnia persistiu mesmo após todas as correções. Em seguida derivamos um painel de marcadores para inferir ancestralidade genética continental, para os componentes ancestrais africano, europeu e ameríndio, e determinamos as proporções de ancestralidade na nossa população de estudo. Na sequência, conduzimos análises de associação entre ancestralidade genética e níveis séricos de lipídios, a fim de estudarmos uma variável menos influenciada por fatores socioeconômicos. Nessas análises encontramos associação entre a ancestralidade ameríndia e níveis séricos de HDL-c. Entender porque essa heterogeneidade existe pode prover importantes pistas sobre as razões para uma importante parte das disparidades étnicas em doenças cardiovasculares / Cardiovascular diseases (CVDs) are the main cause of morbidity and mortality in the world and ethnicity plays an important influence on diagnosis and treatment of these diseases. However, the basis of these ethnic disparities are not fully understood. Studying a population with a high genetic admixture allows potential ways to understand the genetic influence on determination of complex disease phenotypes, such as cardiovascular, in common ancestral roots. The present study had as main aim associating self-reported ethnicity and genetic ancestry in individuals from a Brazilian cohort which have risk factors for cardiovascular diseases. We identified association between self-reported ethnicity and arterial hypertension, stroke, and hypercholesterolemia. Analyzing hypercholesterolemia more deeply, we found association of ethnicity with serum levels of triglycerides (TG), high density lipoprotein cholesterol (HDL-c), and TG/HDL-c index. These associations were strongly dependent on socioeconomic confounders, but there are variations in the strength and direction of each pattern. However, we observed that the ethnicity effect persisted even after all adjustments. Following, we derived a panel of markers to infer continental genetic ancestry for African, European and Amerindian ancestral components, and we have determined the ancestral proportions of ancestry in our study population. After that, we conducted association analysis between genetic ancestry and lipids serum levels, in order to study a variable which is less influenced by socioeconomic factors. In these analyzes we found association between Amerindian ancestry and serum levels of HDL-c. Understanding why there is this heterogeneity can provide important clues about the reason for an important part of ethnic disparities in cardiovascular diseases

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-18T17:47:47Z No. of bitstreams: 1 Danniel Sann Dias da Silva Analise da ancestralidade...2013.pdf: 1290114 bytes, checksum: 95da03014304e202e3b248867ec987a7 (MD5) / Made available in DSpace on 2013-10-18T17:47:47Z (GMT). No. of bitstreams: 1 Danniel Sann Dias da Silva Analise da ancestralidade...2013.pdf: 1290114 bytes, checksum: 95da03014304e202e3b248867ec987a7 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / O carcinoma escamocelular oral (CEO), entre homens, é o quarto câncer mais frequente no Nordeste do Brasil e o terceiro na Bahia. Apesar de possuir etiologia multifatorial, pelo menos 80% dos casos são atribuíveis à exposição ao fumo e ao álcool. Suscetibilidade individual ao CEO tem sido amplamente estudada, e é atribuída a fatores genéticos e também sócio-econômicos. Polimorfismos genéticos de risco, comuns em determinadas populações; hábitos de vida; dificuldade de acesso à informação e aos serviços de saúde são exemplos destes fatores. Sabendo da alta incidência do CEO na Bahia objetivou-se analisar a distribuição dos fatores de risco para CEO numa amostra da população da Bahia. Participaram 332 doadores voluntários de um banco de sangue público baiano, com idade entre 19 e 66 anos. Coletaram-se amostras biológicas de 320 indivíduos e aplicou-se questionário epidemiológico em 309. Investigaram-se cinco polimorfismos de risco (GSTT1*nulo, GSTM1*nulo, CYP1A1*2C (rs1048943), XRCC1 399*Gln (rs25487) eXRCC1 194*Trp (rs1799782) e nove marcadores informativos de ancestralidade (AIMs), por meio de PCR para as inserções e/ou deleções, e PCR-RFLP ou Real Time-PCR para as mutações pontuais. Observou-se presença dos alelos de risco variando entre 12,3% e 56,5% dos indivíduos (XRCC1 194*Trp e XRCC1 399*Gln, respectivamente). A frequência do tabagismo foi 14,6%, etilismo 64,3% (12,7% azem uso abusivo de álcool). Os outros fatores de risco variaram entre 2,3% e 1,3% (relato de HPV e dificuldades de acesso aos serviços de saúde). A estimativa de ancestralidade mostrou maior contribuição ancestral nativo americana em portadores do genótipo GSTM1-nulo que nos não-nulo, o qual foi mais frequente em brancos. Não foi observada associação entre ancestralidade/raça e os fatores de risco ambientais. No entanto, alguns fatores de risco foram associados à baixa renda, e, principalmente, à baixa escolaridade. Contudo, embora a ancestralidade possa influenciar a suscetibilidade genética, não houve influência sobre a suscetibilidade ambiental já que os fatores de risco ambientais se relacionaram principalmente com aspectos socioeconômicos. / The oral squamous cell carcinomas (CEO) is the fourth most common cancer in northeastern Brazil and also in Bahia. Despite having a multifactorial etiology, at least 80% of cases are attributable to exposure to tobacco and alcohol. Individual susceptibility to CEO has been widely studied, and is attributed to genetic and socioeconomic factors. Genetic polymorphisms of risk, common in certain ancestral populations; lifestyle; information access and health services difficulty are examples of such factors. Given the high incidence of CEO in Bahia we investigated the distribution of risk factors for CEO in a sample from Bahia population. Participated in 332 voluntary blood donors of a public blood bank in Bahia, ages ranged from 20 to 66 years. Biological samples was collect from 320 individuals and epidemiological questionnaire was applied to 309. We investigated five polymorphisms of susceptibility (GSTT1*null, GSTM1*null, CYP1A1*2C (rs1048943), XRCC1 399*Gln (rs25487) and XRCC1 194*Trp (rs1799782)) and nine ancestry informative markers (AIMs) by PCR for insertions and/or deletions, and PCR-RFLP and Real Time-PCR for SNP. We observed the presence of risk alleles ranging from 12.3% to 56.5% of subjects (XRCC1 194*Trp and XRCC1-399*Gln, respectively). Smoking was prevalent in 14.6% of subjects, alcoholism in 64.3% (12.7% alcohol abuse). The other risk factors varied between 2.3% and 41.3% (reported HPV and poor access to health services). The ancestry estimative showed high contribution of Native American in individuals with genotype GSTM1*null, which was more common in whites. In this sample, there was no relationship between ancestry/race and environmental risk factors. However, some risk factors were associated with low income, and, especially, low schooling. However, while the ancestry can influence genetic susceptibility, no influence on the environmental susceptibility, which relates mainly to socioeconomic factors.

Doenças cardiovasculares (DCVs) são a principal causa de morbidade e mortalidade no mundo e a etnia do indivíduo tem uma importante influência no diagnóstico e tratamento dessas doenças. No entanto, as bases das disparidades étnicas ainda não estão completamente esclarecidas. O estudo de uma população com alta miscigenação genética, fornece potenciais maneiras de compreender a influência genética na determinação de fenótipos de doenças complexas, como as cardiovasculares, em raízes ancestrais comuns. O presente estudo teve como objetivo principal associar etnia auto referida e ancestralidade genética em indivíduos de uma coorte brasileira com fatores de risco para doenças cardiovasculares. Identificamos associação entre etnia auto referida e hipertensão arterial, acidente vascular cerebral (AVC) e hipercolesterolemia. Analisando a hipercolesterolemia com mais detalhes, encontramos associação de etnia com níveis séricos de triglicerídeos (TG), lipoproteína de alta densidade (HDL-c) e índice TG/HDL-c. Essas associações foram fortemente dependentes de confundidores socioeconômicos, mas variações existem na força e direção de cada padrão. No entanto, observamos que o efeito de etnia persistiu mesmo após todas as correções. Em seguida derivamos um painel de marcadores para inferir ancestralidade genética continental, para os componentes ancestrais africano, europeu e ameríndio, e determinamos as proporções de ancestralidade na nossa população de estudo. Na sequência, conduzimos análises de associação entre ancestralidade genética e níveis séricos de lipídios, a fim de estudarmos uma variável menos influenciada por fatores socioeconômicos. Nessas análises encontramos associação entre a ancestralidade ameríndia e níveis séricos de HDL-c. Entender porque essa heterogeneidade existe pode prover importantes pistas sobre as razões para uma importante parte das disparidades étnicas em doenças cardiovasculares / Cardiovascular diseases (CVDs) are the main cause of morbidity and mortality in the world and ethnicity plays an important influence on diagnosis and treatment of these diseases. However, the basis of these ethnic disparities are not fully understood. Studying a population with a high genetic admixture allows potential ways to understand the genetic influence on determination of complex disease phenotypes, such as cardiovascular, in common ancestral roots. The present study had as main aim associating self-reported ethnicity and genetic ancestry in individuals from a Brazilian cohort which have risk factors for cardiovascular diseases. We identified association between self-reported ethnicity and arterial hypertension, stroke, and hypercholesterolemia. Analyzing hypercholesterolemia more deeply, we found association of ethnicity with serum levels of triglycerides (TG), high density lipoprotein cholesterol (HDL-c), and TG/HDL-c index. These associations were strongly dependent on socioeconomic confounders, but there are variations in the strength and direction of each pattern. However, we observed that the ethnicity effect persisted even after all adjustments. Following, we derived a panel of markers to infer continental genetic ancestry for African, European and Amerindian ancestral components, and we have determined the ancestral proportions of ancestry in our study population. After that, we conducted association analysis between genetic ancestry and lipids serum levels, in order to study a variable which is less influenced by socioeconomic factors. In these analyzes we found association between Amerindian ancestry and serum levels of HDL-c. Understanding why there is this heterogeneity can provide important clues about the reason for an important part of ethnic disparities in cardiovascular diseases

The purpose of this study is to understand what future role archive institutions have for genealogists as a result of genetic ancestry testing. To answer the purpose of this study, three additional research questions have been given. The research questions are as follows (1) what type of information genealogists search for when using genetic ancestry testing (2) what kind of information genealogists are able to retrieve by performing a genetic ancestry test (3) how the archive institutions perceive genealogists who perform genetic ancestry testing. Three different methods have been used to retrieve relevant source material. The methods used are netnography, introspective action research and interviews. The source material has been retrieved by analysing three different discussion forums, interviewing representatives of archive institutions as well as performing genetic ancestry testing ourselves. The theories used in the analyses is based on the theoretical framework established by Martin Saar that involves three dimensions of genealogy, and a secondary framework based on Lisa M. Givens and Donald O. Case’s particular understanding of information behaviour, as well as information seeking. The results of the study have enabled us to conclude three different future scenarios on how the archive institution’s role for genealogists will change. The first conclusion is that the DNA-services will slowly phase out the primary role archives play for the genealogists today. Instead, the commercial DNA-services will become the primary source of information. The second conclusion is that the definition of “value” in regard to the material generated by a genealogist will change, and their research will in the future be seen as valuable by the archive institutions. The third and final conclusion is that the archive institutions will begin to facilitate information and knowledge regarding different aspects of genetic ancestry testing, due to demand of archival users. This is a two-year master’s thesis in Archival Science.