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Investigation génétique de NAFLD dans le diabète de type 2 via construction d’un modèle de prédiction de la maladie et par criblage du locus PNPLA3-SAMM50Attaoua, Redha 07 1900 (has links)
La stéatose hépatique non-alcoolique (NAFLD) est une altération hépatique fréquente dans le diabète de type 2 (DT2) et est associée à diverses complications telles que la mortalité. L’établissement d’outils de prédiction non-invasifs de NAFLD est primordial. Mon projet de maîtrise avait pour objectif d’établir des marqueurs génétiques de NAFLD dans le DT2 via deux stratégies : 1) une sélection non-ciblée des marqueurs génétiques (SNPs) via la méthode LASSO et 2) une sélection ciblée de SNPs rapportés comme liés à la maladie ou à des altérations associées. Une population de 4098 patients avec DT2 d’origine caucasienne (ADVANCE) a été utilisée. Des données statistiques sommaires d’études pangénomiques ont été exploitées pour sélectionner, via LASSO, les marqueurs génétiques (SNPs) à inclure dans le score de risque polygénique (PRS). J’ai également développé un modèle de 3210 SNPs ajusté par des covariables capable de prédire les taux élevés de ALT (AUC=0,69) et la mortalité non-cardiovasculaire (AUC=0,66). Le criblage du locus candidat PNPLA3-SAMM50 a mis en avant une diversité des associations génétiques aux différentes altérations métaboliques comme les taux de ALT (substitut du diagnostic de NAFLD) (rs2294915, P = 1,83x10-7), à la mortalité non-cardiovasculaire (rs2294917, P = 3,9x10-4) et à l’efficacité de la thérapie intensive antidiabétique chez certains patients de la population (porteurs GG de rs16991236, P=0,007). Mes travaux ont permis de mieux comprendre le fond génétique de NAFLD dans le DT2 et laissent envisager l’établissement d’outils de diagnostic et de suivi de la maladie plus adéquats. / Non-alcoholic fatty liver disease (NAFLD) is a liver disorder more frequent in type 2 diabetes (T2D) and is associated with complications such as mortality. For this reason, establishing non-invasive tools for predicting NAFLD is crucial. My master’s project aimed to establish genetic markers for NAFLD in T2D using two strategies: 1) a non-targeted selection of genetic markers (SNPs) by the LASSO method and 2) a targeted selection of SNPs reported as associated with the disease or its related abnormalities. A population involving 4098 patients with T2D and Caucasian ancestry was used. Summary statistics data of pangenomic studies were exploited for the selection of SNPs to be involved in the polygenic risk score (PRS). I also designed a model of 3210 SNPs adjusted by covariates and able to predict the high rates of ALT (AUC=0.69) and non-cardiovascular death (AUC=0.66). Mapping of the candidate locus PNPLA3-SAMM50 allowed the observation of diversity in terms of genetic association with the metabolic abnormalities such as ALT (surrogate of NAFLD) (rs2294915, P = 1.83x10-7), non-cardiovascular death (rs2294917, P = 3.9x10-4) and the efficiency of the intensive antidiabetic therapy within a subgroup in the population (individuals with GG of rs16991236, P = 0.007). My studies allowed for a better understanding of the genetic background of NAFLD in T2D and open perspectives for establishing more adequate tools for diagnosis and follow-up of the disease.
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Physical Activity and Cardiovascular DiseaseAndersen, Kasper January 2014 (has links)
The aim was to investigate associations of fitness and types and levels of physical activity with subsequent risk of cardiovascular disease. Four large-scale longitudinal cohort studies were used. The exposures were different measures related to physical activity and the outcomes were obtained through linkage to the Swedish In-Patient Register. In a cohort of 466 elderly men without pre-existing cardiovascular disease, we found that skeletal muscle morphology was associated with risk of cardiovascular events. A high amount of type I (slow-twitch, oxidative) skeletal muscle fibres was associated with lower risk of cardiovascular events and high amount of type IIx was associated with higher risk of cardiovascular events. This association was only seen among physically active men. Among 39,805 participants in a fundraising event, higher levels of both total and leisure time physical activity were associated with lower risk of heart failure. The associations were strongest for leisure time physical activity. In a cohort of 53,755 participants in the 90 km skiing event Vasaloppet, a higher number of completed races was associated with higher risk of atrial fibrillation and a higher risk of bradyarrhythmias. Further, better relative performance was associated with a higher risk of bradyarrhythmias. Among 1,26 million Swedish 18-year-old men, exercise capacity and muscle strength were independently associated with lower risk of vascular disease. The associations were seen across a range of major vascular disease events (ischemic heart disease, heart failure, stroke and cardiovascular death). Further, high exercise capacity was associated with higher risk of atrial fibrillation and a U-shaped association with bradyarrhythmias was found. Higher muscle strength was associated with lower risk of bradyarrhythmias and lower risk of ventricular arrhythmias. These findings suggest a higher rate of atrial fibrillation with higher levels of physical activity. The higher risk of atrial fibrillation does not appear to lead to a higher risk of stroke. In contrast, we found a strong inverse association of higher exercise capacity and muscle strength with vascular disease. Further, high exercise capacity and muscle strength are related to lower risk of cardiovascular death, including arrhythmia deaths. From a population perspective, the total impact of physical activity on cardiovascular disease is positive.
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