Metabonomics of the blood of pregnant women for diagnosis of prenatal disorders
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(2) Universidade de Aveiro Departamento de Química Ano 2010. Joana Isabel Monteiro Pinto. Metabonomics of the Blood of Pregnant Women for Diagnosis of Prenatal Disorders. Dissertation submitted to the University of Aveiro to fulfil the requirements for the degree of Master in the field of Biomolecular Methods, done under the scientific supervision of Doctor Ana Maria Pissarra Coelho Gil, Associated Professor with Aggregation of the Department of Chemistry of the University of Aveiro.. .. Financial support from FCT through project FCT/PTDC/QUI/66523/2006: An NMR-based metabonomics study of health disorders of foetus and mother during pregnancy: towards biochemical characterisation and early diagnostics.
(3) Examining Commitee President. Prof. Dr.ª Maria do Rosário Gonçalves dos Reis Marques Domingues Auxiliary Professor of the Department of Chemistry of the University of Aveiro. Prof. Dr.ª Isabel Marques Carreira Associated Professor of Cytogenetics Laboratory and CNC of the Faculty of Medicine of the University of Coimbra. Prof. Dr. Brian James Goodfellow Auxiliary Professor of the Department of Chemistry of the University of Aveiro. Prof. Dr.ª Ana Maria Pissarra Coelho Gil Associated Professor with Aggregation of the Department of Chemistry of the University of Aveiro.
(4) Acknowledgements. I would like to express my sincere gratitude to my supervisor Dr. Ana Gil for giving me the opportunity to carried out this work and experience first hand the scientific research. I thank for her guidance, help and availability. I would like to especially acknowledge Dr. António Barros for kindly helping me with multivariate analysis. My gratitude also goes to Gonçalo Graça for contributing to this work with the NMR experiments and his indispensable help to analyse the resulting data, and to João Rodrigues for helping me with FTIR spectroscopy experiments and data analysis. I would also like to acknowledge to everyone in the Metabonomics Group of the University of Aveiro who directly or indirectly have contributed to the work presented here. I wish to knowledge the Fundação para a Ciência e Tecnologia (FCT) for their financial support through the research project FCT/PTDC/QUI/66523/2006: An NMR-based metabonomics study of health disorders of foetus and mother during pregnancy: towards biochemical characterisation and early diagnostics. I would like to acknowledge the Prenatal Diagnosis Service in Bissaya Barreto Maternity and the Cytogenetics Laboratory of the Faculty of Medicine in Coimbra for the important contribution to the project FCT/PTDC/QUI/66523/2006. I also acknowledge the Chemistry Department of University of Aveiro for providing the physical conditions for this work. Finally, I thank to my mother for her patience and to my all family and friends..
(5) Palavras-chave. Metabonómica, Diabetes Gestacional, Malformações Fetais, Plasma Sanguíneo, Ressonância Magnética Nuclear, Infravermelho com Transformadas de Fourier, Análise Multivariada.. Resumo. A aplicação da metabonómica na pesquisa de novos biomarcadores de doenças tem ganho um interesse crescente na investigação e desenvolvimento, tanto ao nível do processamento analítico como do tratamento de dados. Nomeadamente, a análise metabonómica usando espectroscopia de Ressonância Magnética Nuclear (NMR) fornece uma grande quantidade de dados de uma forma rápida e não invasiva sobre a composição de amostras complexas como o plasma sanguíneo. Uma vez que as doenças pré-natais têm um elevado impacto no metabolismo materno e fetal, sendo responsáveis por várias complicações durante e depois da gravidez, esta estratégia foi aplicada ao estudo destas doenças através da análise de sangue de senhoras grávidas (colhido entre 15-24 semanas de gestação), com o objectivo de investigar possíveis metabolitos marcadores ou com poder de previsão para a diabetes gestacional e malformações fetais. Num primeiro passo, foram estudados os perfis metabólicos em RMN dos controlos (n=20) e gravidezes com diagnóstico ou suspeita de malformações fetais (n=11) e pré-diabetes gestacional (com posterior diagnóstico clínico entre 22-34 semanas de gestação). A análise multivariada (análise de componentes principais, PCA; análise discriminante pelo método de mínimos quadrados parcias, (PLS-DA) e duas versões deste último, interval PLS-DA e ortogonal PLS-DA (OPLS-DA)) foram aplicados com o objectivo de pesquisar por correlações de solidez estatística entre a composição do plasma e a ocorrência das doenças em estudo. Os resultados mostraram que as amostras controlo e doença podem ser diferenciadas com base no seu perfil metabólico, nomeadamente mostrando níveis mais elevados de compostos que contêm colina em mulheres que desenvolveram diabetes gestacional mais tarde na gravidez. Adicionalmente, níveis mais elevados de piruvato, manose e compostos que contêm colina, e níveis mais baixos de vários aminoácidos e acetato foram encontrados nas gravidezes afectadas por malformações fetais. Numa segunda etapa do trabalho, as mesmas amostras foram analisadas por espectroscopia de Infravermelho com Transformadas de Fourier (FTIR), um método mais barato e acessível para eventual uso clínico. O perfil dos espectros de FTIR também revelou algumas diferenças entre controlos e doenças, no entanto a sua interpretação específica torna-se difícil devido à grande sobreposição de bandas característica de espectros de infravermelho. Estes resultados mostraram que a análise metabonómica de plasma de mulheres grávidas por RMN e FTIR pode ser uma ferramenta poderosa para obter informação bioquímica sobre a saúde pré-natal e encontrar possíveis novos marcadores com potencial para prever doenças, particularmente no caso do diabetes gestacional..
(6) Keywords. Metabonomics, Gestational Diabetes, Fetal malformations, Blood Plasma, Nuclear Magnetic Resonance, Fourier Tansform Infrared, Multivariate Analysis.. Abstract. The use of Metabonomics to search for new disease biomarkers has gained increasing interest in the research community and continuous developments, both at the analytical and data processing levels have boosted this area into new quests in biomarker research. Namely, Nuclear Magnetic Resonance (NMR)-metabonomics provides a large amount of compositional data on complex samples such as blood plasma, in a rapid and non-invasive manner. Since prenatal diseases have a high impact on both maternal and fetal metabolisms, being responsible for a range of complications both during and after pregnancy, this strategy was hereby applied to the study of prenatal diseases, through the analysis of blood (collected at 15-24 gestational weeks), in order to probe for possible marker/predictor metabolites for gestational diabetes and fetal malformations. In the first stage of this work, the plasma metabolic profiles of controls (n=20) and pregnancies affected by diagnosed or suspected fetal malformations (n=11) and pre-gestational diabetes (with posterior clinical diagnosis at 22-34 gestational weeks) were evaluated by NMR spectroscopy. Multivariate analysis (principal component analysis, PCA; partial least squares discriminant analysis, PLS-DA and two extended versions of the latter, interval PLS-DA (iPLS-DA) and orthogonal PLS-DA (OPLS-DA) were applied in order to search for consistent statistical correlations between plasma composition and the occurrence of the diseases. It was found that controls and diseased subjects could be differentiated with basis on their plasma profile, namely showing higher levels of choline-containing compounds in pregestational diabetic women. In addition, higher contents of pyruvate, mannose and choline-containing compounds and lower contents of several amino acids and acetate were found in pregnancies affected by fetal malformations. In a second stage of the work, the same samples were analysed by Fourier Transform Infrared (FTIR) spectroscopy, a cheaper and more-accessible method, more suited to straightforward clinical use. The FTIR spectral profiles also revealed some differences between controls and diseased subjects, the interpretation of which posing a harder challenge than that of NMR. These results have shown that NMR and FTIR metabonomics of pregnant women blood plasma may be a powerful tool to gain insight into prenatal diseases and find possible new markers with potential predictive value, particularly in the case of gestational diabetes..
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