Yes / Personalized medicine through Pharmacogenomics: choosing the right drug, and the right dose, for the right patients based on patient’s genetic makeup-is gradually being realised in Western countries. Yet, the practice of pharmacogenomics in Asian countries lags behind that of the West, but the medical needs for pharmacogenomics are expected to surge as better patient care is demanded in Asia. As next-generation sequencing technology advances quickly, previous technical challenges for performing pharmacogenomic studies or practices in Asia have been mostly resolved. What is lacking in Asia is an effective model of community-wide pharmacogenomics. On the delivery front, pharmacists, the drug and dosing professionals, can potentially be the main healthcare providers for pharmacogenomic services in Asia. The first large “Genomics for Precision Drug Therapy in the Community Pharmacy” in Canada, which is close to its completion, has successfully identified community pharmacists as key contact professionals for smooth facilitation and implementation of pharmacogenomics for personalized medication. It is anticipated that Asian pharmacists, with appropriate training, can have the capacity to provide expert pharmacogenomic supports for both physicians and patients in Asia. / The School of Biomedical Sciences Start-up Fund, the Chinese University of Hong Kong, the General Research Fund (#17114814; #17121616), the Theme-based Research Scheme (T12-401/13-R), Research Grant Council, Hong Kong, as well as the Hong Kong Cancer Fund, Hong Kong.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-11T14:30:43Z No. of bitstreams: 1 Cyntia Cajado de Souza.pdf: 4771962 bytes, checksum: bdc7d5b7181b8a72749dc6d7de91f2f3 (MD5) / Made available in DSpace on 2013-10-11T14:30:43Z (GMT). No. of bitstreams: 1 Cyntia Cajado de Souza.pdf: 4771962 bytes, checksum: bdc7d5b7181b8a72749dc6d7de91f2f3 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / A anemia falciforme (HbSS) é uma doença genética com prevalência mundial elevada, caracterizada pela heterogeneidade clinica apresentando manifestações agudas e crônicas de caráter multifatorial, sendo caracterizada pela presença do estado inflamatório sistêmico. As alterações no sistema imune têm sido relacionadas a predisposição a infecções em pacientes HbSS, com produção exacerbada de anticorpos, alterações na função de leucócitos e na imunidade celular, entre outros. Estão inclusos nesta tese o conjunto de três manuscritos com o objetivo de investigar marcadores genéticos relacionados a inflamação em pacientes com HbSS, com ênfase para os polimorfismo e níveis séricos das citocinas TNFα -308G>A e IL-8 251A>T, para a provável influência dos polimorfismos gênicos TNFα-308G>A, FcRIIAH/R131, MPO-463G>A, TLR4 896A>G, e TLR9- 1237T>C na gravidade de infecções e complicações inflamatórias na HbSS, e ainda a expressão gênica dos receptores TLR2, TLR4, TLR5 e TLR9 em células dendríticas de pacientes HbSS. Nossos resultados mostraram que os níveis séricos elevados das citocinas TNFα e IL-8, bem como a presença do alelo mutante dos polimorfismos de TNFα e da IL-8 estudados estão associados com a gravidade clínica da doença. O estudo dos polimorfismos TLR9 -1237T>C e TLR4 896A>G mostraram associação com a ocorrência de infecção respiratória e acidente vascular encefálico (AVE), respectivamente, e o polimorfismo MPO-463G>A esteve associado com a ocorrência de infecções. Além disso, a presença concomitante do polimorfismo FcRIIA H/R131 com o MPO-463G>A, com o TLR4 896A>G, ou com o TNF-α influenciou a ocorrência de internações hospitalares, de sequestro esplênico, de AVE e do número de crises vaso-oclusivas. O estudo de novos marcadores de inflamação na anemia falciforme pode ajudar no entendimento da complexidade da fisiopatologia desta doença. Nossos dados enfatizam a identificação de novos biomarcadores genéticos e sua associação marcadores clássicos podem ser uma ferramenta importante para elucidar a diversidade fenotípica da HbSS. / Sickle cell anemia (HbSS) is a genetic disease with elevated worldwide distribution characterized by clinical heterogeneity and acute and chronic complication presenting systemic inflammatory state. The immune system changes are related to infection predisposition in HbSS, exacerbated antibody production, changes in leucocytes function and innate immunity. It was included in this thesis a set of three manuscripts that aim to investigate genetic markers related to inflammation in HbSS emphasizing polymorphisms and cytokine serum levels of TNFα -308G>A and IL-8 251A>T, to the influence of genetic polymorphisms of TNFα-308G>A, FcRIIAH/R131, MPO-463G>A, TLR4 896A>G and TLR9- 1237T>C in infection and inflammatory complication in HbSS and the gene expression of dendritic cell TLR2, TLR4, TLR5 and TLR9 receptors. Our results shows high serum levels and the presence of TNFα and IL-8 mutant allele were related to disease clinical severity. The study of TLR9 -1237T>C and TLR4 896A>G polymorphisms were associated to respiratory infection and encephalic vascular accident (EVA), respectively, and the polymorphism MPO-463G>A was associated to infection. The double presence of polymorphism FcRIIA H/R131 with MPO-463G>A or with TLR4 896A>G or with TNF-α influence the presence of hospitalization, spleen sequestration, EVA and vasooclusive crisis. The new sickle cell anemia inflammation markers study may help to highlight the disease physiopathology complexity. Our finds emphasizes new genetic and immunological biomarkers identification and its association with classical markers may be important to elucidate phenotypic HbSS diversity.

L’hyperchylomicronémie familiale est un trait monogénique caractérisé par un taux de triglycérides plasmatiques à jeun supérieur à 10 mmol/L (la normale étant de 1,7 mmol/L). L’hyperchylomicronémie familiale est le plus souvent causée par une déficience dans le gène LPL (pour lipoprotéine lipase). La déficience en lipoprotéine lipase (LPLD) est aussi associée à un risque élevé de pancréatite. La pancréatite en soi est reconnue comme un trait complexe génétique dont plusieurs gènes sont associés à sa susceptibilité. Étant donné l’expression variable de la pancréatite chez les patients LPLD, les résultats de ce mémoire présentent certains facteurs génétiques pouvant être responsables du risque de l’expression de la pancréatite aigüe récurrente chez les sujets LPLD. L’analyse par séquençage des régions codantes et promotrices des gènes CTRC (pour « Chymotrypsin C ») et SPINK1 (pour « Serine protease inhibitor Kazal type 1 ») a été effectuée chez 38 patients LPLD et 100 témoins. Ces deux gènes codent pour des protéines impliquées dans le métabolisme des protéases au niveau du pancréas et ont déjà été associés avec la pancréatite dans la littérature. Notre étude a permis d’identifier une combinaison de deux polymorphismes (CTRC-rs545634 et SPINK1-rs11319) associée significativement avec la récidive d’hospitalisations pour douleur abdominale sévère ou pour pancréatite aigüe récurrente chez les patients LPLD (p<0,001). Ces résultats suggèrent que le risque de récidive de pancréatite chez les patients LPLD peut être influencé par des variants dans des gènes de susceptibilité à la pancréatite. L’identification de biomarqueurs génétiques améliore la compréhension des mécanismes physiopathologiques de la pancréatite chez les patients LPLD ce qui, par conséquent, permet de mieux évaluer et caractériser les risques de pancréatite afin d'adapter un plan d'intervention préventif pour ces patients. / Familial hyperchylomicronemia is a monogenic trait characterized by an increased fasting plasma triglyceride levels ≥ 10 mmol/L (normal is 1.7 mmol/L). Familial hyperchylomicronemia is most often caused by a deficiency in the LPL gene. Lipoprotein lipase deficiency (LPLD) is also associated with an increased risk of pancreatitis. Pancreatitis is recognized as a complex genetic trait and several genes are associated with its susceptibility. Considering the variable expression of pancreatitis in LPLD patients, results of this manuscript demonstrate that genetic factors may be responsible of the increased risk of recurrent acute pancreatitis episodes in LPLD subjects. The sequencing analysis of the coding and promoters regions of CTRC gene (for Chymotrypsin C) and SPINK1 gene (for Serine protease inhibitor Kazal type 1) was performed. These two genes encode proteins involved in the metabolism of the pancreas proteases and have been associated with pancreatitis in literature. A combination of two polymorphisms (CTRC-rs545634 and SPINK1-rs11319) have been identified and associated with recurrent hospitalizations for severe abdominal pain or recurrent acute pancreatitis in LPLD patients (p <0.001). These results suggest that the risk of recurrent episodes of pancreatitis in LPLD patients may be influenced by variants in susceptibility genes. The identification of genetic biomarkers improves the understanding of the pathophysiological mechanisms of pancreatitis in LPLD patients which therefore helps to assess and characterize the risk of pancreatitis to adapt preventive intervention plan for these patients.