Variabilidade genética na população brasileira : ancestralidade genômica e fenótipos de capacidade cardiovascular

O processo de miscigenação recente entre diferentes populações ancestrais pode levar a obtenção de resultados espúrios em estudos de associação genética. A estratificação pela classificação de cor de pele é uma ferramenta útil para controle de estrutura populacional, mas, para a população brasileira, alguns estudos demonstraram que este método de estratificação por classificação de cor de pele não é uma estratégia funcional, pois há uma dissociação entre a cor de pele autorrelatada e a ancestralidade genômica. No primeiro capítulo desta pesquisa, foram reportados resultados de um estudo em um grupo de irmãs germanas brasileiras, no qual a pigmentação de pele constitutiva foi mensurada utilizando-se um refratômetro, a ancestralidade genômica foi estimada pela genotipagem de 21 marcadores informativos de ancestralidade (AIMs) e a cor de pele autorrelatada foi avaliada de acordo com classificação adotada pelo censo demográfico brasileiro em cada participante. Foi explorada a associação entre cor de pele e pigmentação constitutiva, cor de pele e ancestralidade genômica, e pigmentação constitutiva e ancestralidade genômica, sendo observado que, apesar de haver diferenças significativas da ancestralidade genômica e da pigmentação entre as três classificações de cor de pele, há uma considerável dispersão dentro de cada grupo e uma grande sobreposição destas variáveis entre os grupos. Foi também observado que não houve uma boa concordância para as três categorias de cor de pele nos pares de irmãs e que o nível socioeconômico associou-se significativamente com a cor de pele autorrelatada e com a ancestralidade genômica. Adicionalmente, foi observada forte associação entre o rs1426654 (localizado no gene SLC24A5 e presente no painel de AIMs utilizado) e a pigmentação de pele constitutiva na presente amostra. Sendo assim, o primeiro capítulo mostrou que classificações subjetivas baseadas na cor de pele autorrelatada são inadequadas para descrever a estrutura populacional presente em populações recentemente miscigenadas. O segundo capítulo reporta a investigação do pico de potência aeróbia (VO2pico), mensurado por ergoespirometria em um teste incremental, com 12 SNPs do sistema renina angiotensina aldosterona (SRAA) em mulheres idosas posmenopausadas, ajustando-se a análise para idade, percentual de gordura e massa livre de gordura, mensuradas por absortometria de raios X de dupla energia. Apesar da não observação de associações estatisticamente significativas após correção para comparações múltiplas pelo índice de falsas descobertas (FDR, do inglês false discovery rate), foram detectadas tendências de associações para os fenótipos cardiovasculares na análise de cada marcador genético individualmente. Também foram observadas tendências de associação na análise de efeitos epistáticos entre combinações genotípicas de 3 SNPs com o VO2pico e com o componente principal calculado a partir do teste cardiorrespiratório. Em síntese, apesar das dificuldades em explicar a herdabilidade para fenótipos complexos atualmente demostrada pelos estudos de genoma total, o segundo capítulo desta pesquisa assinalou algumas possíveis contribuições genéticas do SRAA para a capacidade cardiovascular.The process of recent admixture between ancestral populations can lead to spurious results in genetic association studies. Stratifying by skin color is a useful method to control for population structure, but, in the Brazilian population, several studies have demonstrated that stratifying according to color is not a suitable strategy, due to the dissociation between selfreported skin color and genomic ancestry. In the first chapter of this research we report the results of a study in a group of Brazilian siblings in which we measured skin pigmentation using a reflectometer, and estimated genomic ancestry using 21 Ancestry Informative Markers (AIMs). Self-reported color, according to the Brazilian census, was also available for each participant to explore the relationship between self-reported color and skin pigmentation, self-reported color and genomic ancestry, and skin pigmentation and genomic ancestry. We observed that, although there were significant differences between the three color groups in genomic ancestry and skin pigmentation, there was considerable dispersion within each group and substantial overlap between groups. We also saw that there was no good agreement between the color categories reported by each member of the sibling pair and that socioeconomic status was significantly associated with self-reported color and genomic ancestry. Also, we observed that rs1426654 (gene SLC24A5 from the AIM panel) was strongly associated with constitutive skin pigmentation in this sample. Hence, this chapter shows that subjective classifications based on self-reported color are inadequate to describe the population structure present in recently admixed populations. The second chapter report the investigation of peak oxygen uptake (VO2peak) measured by ergoespirometric graded test with 12 SNPs markers of the renin angiotensin aldosterone system (RAAS) in postmenopausal elderly, adjusting for age, fat percentage and fat free mass measured by dual-energy X-ray absorptiometry. In despite of no observation of significant associations after correction for multiple comparisons by the false discovery rate (FDR) method, there was detected some borderline associations with the cardiovascular phenotypes in the analysis of each marker individually and some borderline associations of epistatic analysis of three SNPs genotype combinations with a principal component calculated from the cardiorespiratory test and with the VO2peak. In summary, even with the difficulties to explain heritability for complex phenotypes, demonstrated by genome wide studies, the second chapter highlighted some possible genetic contributors to the cardiovascular fitness in the RAAS.The process of recent admixture between ancestral populations can lead to spurious results in genetic association studies. Stratifying by skin color is a useful method to control for population structure, but, in the Brazilian population, several studies have demonstrated that stratifying according to color is not a suitable strategy, due to the dissociation between selfreported skin color and genomic ancestry. In the first chapter of this research we report the results of a study in a group of Brazilian siblings in which we measured skin pigmentation using a reflectometer, and estimated genomic ancestry using 21 Ancestry Informative Markers (AIMs). Self-reported color, according to the Brazilian census, was also available for each participant to explore the relationship between self-reported color and skin pigmentation, self-reported color and genomic ancestry, and skin pigmentation and genomic ancestry. We observed that, although there were significant differences between the three color groups in genomic ancestry and skin pigmentation, there was considerable dispersion within each group and substantial overlap between groups. We also saw that there was no good agreement between the color categories reported by each member of the sibling pair and that socioeconomic status was significantly associated with self-reported color and genomic ancestry. Also, we observed that 1426654 (gene SLC24A5 from the AIM panel) was strongly associated with constitutive skin pigmentation in this sample. Hence, this chapter shows that subjective classifications based on self-reported color are inadequate to describe the population structure present in recently admixed populations. The second chapter report the investigation of peak oxygen uptake (VO2peak) measured by ergoespirometric graded test with 12 SNPs markers of the renin angiotensin aldosterone system (RAAS) in postmenopausal elderly, adjusting for age, fat percentage and fat free mass measured by dual-energy X-ray absorptiometry. In despite of no observation of significant associations after correction for multiple comparisons by the false discovery rate (FDR) method, there was detected some borderline associations with the cardiovascular phenotypes in the analysis of each marker individually and some borderline associations of epistatic analysis of three SNPs genotype combinations with a principal component calculated from the cardiorespiratory test and with the VO2peak. In summary, even with the difficulties to explain heritability for complex phenotypes, demonstrated by genome wide studies, the second chapter highlighted some possible genetic contributors to the cardiovascular fitness in the RAAS