Introdução: A Hipercolesterolemia Familiar (HF) é uma doença genética caracterizada clinicamente por elevados níveis de lipoproteína de baixa densidade (LDL-C) na corrente sanguínea desde a infância. Indivíduos que apresentam HF podem desenvolver doença aterosclerótica ainda em idade jovem. Os principais preditores de risco no desenvolvimento da doença cardiovascular (DCV) nesses indivíduos após entrarem em um programa de rastreamento genético não são conhecidos na nossa população. Além disso, a HF é subdiagnosticada e subtratada mundialmente e o rastreamento genético em cascata dos familiares tem sido mundialmente avaliado como o método diagnóstico mais custo. Contudo, a efetividade do rastreamento genético em cascata é dependente dos critérios clínicos de entrada do primeiro indivíduo da família e não há um consenso de qual critério apresenta a melhor acurácia para detecção de uma mutação. Objetivos: Identificar os fatores determinantes para ocorrência de eventos cardiovasculares (CV) em todos os indivíduos da coorte e avaliar o critério clínico para detecção de uma variante genética patogênica para HF, no primeiro indivíduo da família, após serem inseridos em um programa de rastreamento genético em cascata.Métodos: Estudo de coorte prospectiva aberta dos pacientes que foram inseridos no programa de rastreamento genético em cascata para HF. A população do estudo é definida como caso índice (CI), o primeiro da família a ser identificado clinicamente e encaminhado para o teste genético, e os familiares, que são os parentes de 1º grau do CI em que foi encontrada uma alteração genética. Todos os indivíduos são inseridos na coorte no momento em que recebem o laudo genético (tempo zero, T0). Um ano depois do T0 é realizado o primeiro contato telefônico, ou seja, primeiro ano de seguimento (T1) Resultados: No T1, o total de 818 indivíduos foi incluído, sendo verificados 47 eventos CV, sendo 14 (29,7%) fatais. Para o CI, o único fator independente associado ao aumento do risco de eventos CV no T1 foi a presença de arco corneano (OR: 9,39; IC 95%: 2,46-35,82). Para os familiares com uma mutação positiva os fatores associados ao aumento do risco de eventos CV foram diabetes mellitus (OR: 7,97; IC 95%: 2,07-30,66) e consumo de tabaco (OR: 3,70; IC 95%: 1,09-12,50). Na análise do melhor critério clínico para detecção de uma mutação patogênica no CI os valores de LDL-C >= 230 mg/dL tiveram a melhor relação entre sensibilidade e especificidade. Na análise da curva ROC o escore Dutch Lipid Clinic Network (DLCN) apresentou melhor desempenho do que o LDL-C para identificar uma mutação, a área sob a curva ROC foi 0,744 (IC 95%: 0,704-0,784) e 0,730 (IC 95%: 0,687-0,774), respectivamente, p = 0, 014. Conclusão: Em um ano de seguimento essa coorte identificou uma alta incidência de eventos CV após a entrada em um programa de rastreamento genético em cascata e os preditores dos eventos CV diferem entre CI e familiares. Esses resultados podem contribuir para o desenvolvimento de ações preventivas nesse grupo altamente susceptível de indivíduos. Além disso, devido a importância da detecção da mutação para um diagnóstico definitivo de HF e a importância da cascata ser custo efetiva o estudo identificou que o critério único do LDL-C >= 230 mg/dl é viável para indicar o CI para o teste genético / Introduction: Familial Hypercholesterolemia (FH) is a genetic disease characterized clinically by high levels of low density lipoprotein (LDL-C) in the bloodstream since childhood. Individuals with FH can develop atherosclerotic disease at a young age. The main predictors of cardiovascular disease (CVD) risk in these individuals after entering a genetic screening program are not known in our population. In addition, FH is underdiagnosed and undertreated worldwide and cascaded genetic screening of family members has been evaluated globally as the most cost effective for the diagnosis of FH. However, the effectiveness of cascading genetic screening is dependent on the clinical entry criteria of the first individual in the family and there is no consensus as to which criterion shows the best accuracy for detecting a mutation. Objectives: To identify the determinant factors for cardiovascular (CV) events in all individuals in the cohort and to evaluate the clinical criteria for detecting a genetic variant pathogenic to FH in the first individual of the family after being inserted into a genetic screening program in cascade. Methods: Open prospective cohort study of patients who were enrolled in the cascade genetic screening program for FH. The study population is defined as index case (IC), the first of the family to be clinically identified and referred to the genetic test, and relatives, who are the first-degree relatives of the IC in which a genetic alteration was found. All individuals are inserted into the cohort at the moment they receive the genetic report (time zero, T0). The first follow-up telephone contact is made one year after T0 (first year of follow-up, T1). Results: In T1, a total of 818 subjects were included, and 47 CV events were verified, of which 14 (29.7%) were fatal. For IC, the only factor independently associated with the increased risk of CV events in T1 was the presence of a corneal arch (OR: 9.39; 95% CI: 2.46-35.82). For relatives with positive mutation, factors associated with increased risk of CV events were diabetes mellitus (OR: 7.97; 95% CI: 2.07-30.66) and tobacco consumption (OR: 3.70; 95% CI: 1.09-12.50). In the analysis of the best clinical criteria for the detection of a pathogenic mutation in the IC, the LDL-C values >= 230 mg/dL had the best relationship between sensitivity and specificity. In the ROC curve analysis, the Dutch Lipid Clinic Network (DLCN) score performed better than LDL-C to identify a mutation, the area under the ROC curve was 0.744 (95% CI: 0.704-0.784) and 0.730 (CI 95 %: 0.687-0.774), respectively, p = 0.014. Conclusion: At one year follow-up this cohort identified a high incidence of CV events following entry into a cascade genetic screening program and the predictors of CV events differ between IC and family members. These results may contribute to the development of preventive actions in this group highly susceptible to individuals. In addition, because of the importance of detecting the mutation for a definitive diagnosis of HF and the importance of the cascade being cost effective, the study identified that the single LDL-C criterion >= 230 mg / dl is feasible to indicate IC for the genetic test

A hipercolesterolemia familiar (HF) é uma doença autossômica dominante caracterizada por níveis elevados de LDL-c e doença arterial coronária (DAC) precoce. Existem evidências de maior prevalência de aterosclerose subclínica nesta população avaliada pelo escore de cálcio (CAC) e pela espessura íntima-média carotídea (EIMC). O objetivo do nosso estudo foi avaliar aterosclerose subclínica por meio da angiotomografia de coronárias em portadores de HF sem aterosclerose manifesta, correlacionando os achados com parâmetros clínicos, laboratoriais, rigidez aórtica e carotídea e com a EIMC. Incluímos 102 HFs, (45±13 anos, 36% homens, LDL-c 280±54mg/dL) e 35 controles (46±12 anos, 40% homens, LDL-c 103±18mg/dL). O grupo HF apresentava maior carga de placa aterosclerótica representado por: maior número de pacientes com placa (48% versus 14%, p=0,0005), maior número de pacientes com estenose luminal acima de 50% (19% versus 3%, p=0,015), maior número total de segmentos com placas (2,0±2,8 versus 0,4±1,3, p=0,0016), maior número de segmentos com placas calcificadas (0,8±1,54 versus 0,11±0,67, p= 0,0044) e maior escore de cálcio pelo método de Agatston (55±129, mediana:0 versus 38±140, mediana:0; p=0,0028). Houve correlação positiva no grupo HF do número total de segmentos com placa com: idade (r=0,41, p<0,0001), escore de risco de Framingham (r=0,25, p=0,012), colesterol total (r=0,36, p<0,0002), LDL-c (r=0,27, p=0,005), HDL-c (r=0,24, p=0,017), apolipoproteína B (r=0,3, p=0,0032) e escore de cálcio (r=0,93, p<0,0001). Além disso, houve correlação negativa com: variação sísto-diastólica carotídea (r=-0,23, p=0,028) e percentual de distensão carotídeo (r=-0,24, p=0,014). A análise multivariada de determinantes da presença de placa aterosclerótica, revelou que idade (OR=1,105, IC95%: 1,049-1,164, p<0,001) e colesterol total (OR=1,013, IC95%:1,001-1,025) foram as variáveis associadas com a presença da mesma. A única variável associada com presença de obstrução luminal acima de 50% foi o escore de cálcio coronário (OR=1,004; IC95%:1,001-1,008; p=0,014). Em relação a determinantes da composição de placa, na análise multivariada a presença de placa não calcificada esteve associada com o sexo masculino (OR:15,45; IC95%: 1,72-138,23, p=0,014), a placa mista com antecedente familiar de DAC precoce (OR=4,90; IC95%:1,32-18,21, p=0,018) e placa calcificada a menor chance com o sexo masculino (OR=0,21; IC95%: 0,05-0,84, p=0,027). Conclusões: Os pacientes portadores de HF apresentam maior carga de placa avaliada pela angiotomografia em comparação aos controles; idade e colesterol total associaram-se a presença de placas no grupo HF; o escore de cálcio associou-se a presença de estenose luminal acima de 50%. / Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by high LDL-c levels and premature coronary artery disease (CAD) onset. There is evidence of greater prevalence of subclinical atherosclerosis in this population evaluated by coronary calcium score (CCS) and carotid intima-media thickness (IMT). The aim of our study was to assess subclinical atherosclerosis by computed tomography coronary angiography (CTCA) in patients with FH without manifest atherosclerosis and correlate the findings with clinical and laboratory parameters, aortic and carotid stiffness and IMT. We included 102 FHs (45 ± 13 years, 36% men, LDL-c 280 ± 54mg/dL) and 35 controls (46 ± 12 years, 40% men, LDL-c 103 ± 18mg/dL). The FH group had a greater atherosclerosis plaque burden represented by: higher number of patients with coronary plaque (48% versus 14%, p = 0.0005) and with luminal stenosis greater than 50% (19% versus 3% p = 0.015), higher total number of segments with plaques (2.0 ± 2.8 versus 0.4 ± 1.3, p = 0.0016), higher number of segments with calcified plaques (0.8 ± 1.54 versus 0.11 ± 0.67, p = 0.0044) and higher CCS by the Agatston method (55 ± 129, median: 0 vs. 38 ± 140, median = 0, p = 0.0028). There were positive correlations of total number of segments with plaque in FH group with the following variables: age (r=0.41, p<0.0001), Framingham risk score (r =0.25, p=0.012), total cholesterol (r=0.36, p<0.0002), LDL-c (r=0.27, p=0.005), HDL-c (r=0.24, p=0.017), apolipoprotein B (r=0,3, p=0.0032) and CCS (r=0.93, p<0.0001). In addition there was a negative correlation with: carotid systo-diastolic variation (r=- 0.23, p=0.028) and percentage of carotid distension (r=- 0.24, p=0.014). After multivariate analysis, the determinants of plaque presence were age (OR=1.105, 95% CI=1.049-1.164, p<0.001) and total cholesterol (OR=1.013, 95% CI:1.001-1.025). The only variable associated with presence of luminal stenosis greater than 50% was CCS (OR = 1.004, 95% CI: 1.001-1.008, p=0.014). After multivariate analysis, the presence of non-calcified plaque was associated with male gender (OR: 15.45, 95% CI 1.72-138.23, p = 0.014), mixed plaque with family history of early CAD (OR = 4.90, 95%:1.32-18.21, p=0.018) and calcified plaque negatively with males (OR = 0.21, 95% CI: 0.05-0.84, p = 0.027). Conclusions: FH subjects have higher plaque burden assessed by CTCA compared to controls; age and total cholesterol were associated with the presence of coronary plaque in the FH subjects; CCS was associated with luminal stenosis greater than50%.

A hipercolesterolemia familiar (HF) é uma alteração de origem genética comum que pode se manifestar clinicamente desde o nascimento e provoca um aumento nos níveis plasmáticos de LDL-colesterol (LDL-c), xantomas e doença coronária prematura. Sua detecção e tratamento precoce reduzem a morbidade e mortalidade coronária. A identificação e rastreamento em cascata familiar usando níveis de LDL-c e detecção genética é a estratégia mais aconselhável e rentável para descoberta de novos casos. O tratamento crônico com estatinas reduz o risco cardiovascular da população em geral, contudo, estudos clínicos com estatinas revelam risco cardiovascular residual mesmo após correção das concentrações de LDL-c. Com o surgimento de novas drogas e mais recentemente um inibidor da enzima pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9), este estudo enfatizou na investigação específica para aqueles acometidos com defeitos genéticos nessa enzima, por ser de frequência ainda mais rara e pouco estudada, necessitando de melhor investigação na população em estudo a fim de rastrear a ocorrência de mutações patológicas na PCSK9. O objetivo desse estudo foi identificar e caracterizar mutações e/ou deleções patológicas no gene PCSK9 em pacientes com Hipercolesterolemia Familiar provenientes do Hospital das Clínicas de Ribeirão Preto da FMRP/USP selecionados para o teste genético. Foi feito o rastreamento de mutações pelo método Hight Resolution Melting (HRM), de forma prática, rápida e eficiente, onde mutações detectadas foram seqüenciadas. Foram identificadas 7 mutações não patogênicas, caracterizando que a população estudada não apresenta Hipercolesterolemia Familiar associada a mutações no gene PCSK9, fato que não exclui o diagnóstico por outros defeitos genéticas associados a doença. / Familial hypercholesterolemia (FH) is an alteration of common genetic origin that can manifest clinically from birth and which causes an increase in the LDL-cholesterol plasma levels (LDL-c), xanthomas and premature coronary disease. Its early detection and treatment reduce morbidity and coronary mortality. The identification and tracking in familial cascade using levels of LDL-c and genetic detection is the most advisable and profitable strategy to find new cases. The chronic treatment with statins reduces the cardiovascular risk in the population in general. However, clinic studies on statins show a residual cardiovascular risk even after the correction of LDL-c concentrations. With the appearance of new drugs and, more recently, of a proprotein convertase subtilisin/kexin type 9 enzyme inhibitor (PCSK9), this study highlighted the specific investigation for those stricken by genetic defects in this enzyme, once it is even rarer and understudied and needs further investigation in the study\'s population aiming at tracking the occurrence of a pathological mutation in the PCSK9. This study aimed at identifying and characterizing mutations and/or pathological deletions in the PCSK9 gene in patients with Familial Hypercholesterolemia from the RPMS/USP Ribeirão Preto Clinical Hospital which were selected for the genetic test. We performed the mutation tracking by using the High Resolution Melting (HRM) method in a practical, fast and efficient way, where the mutations detected were sequenced. We identified 7 non-pathogenic mutations, showing that the population studied does not present Familial Hypercholesterolemia associated to mutations in the PCSK9 gene, which doesn\'t exclude the diagnosis by other genetic defects associated to the disease.

A hipercolesterolemia familiar (HF) é uma doença de herança genética autossômica dominante caracterizada pela elevação dos níveis séricos de colesterol total e das lipoproteínas de baixa densidade (LDL- c). Conhecida por estar estreitamente relacionada ao processo aterosclerótico, a HF pode determinar o desenvolvimento de lesões obstrutivas precoces em distintos leitos arteriais. Nesse contexto, a HF também tem sido proposta como um fator de risco para a doença arterial periférica (DAP). Avaliamos assim de forma sistemática por meio de um estudo transversal e observacional, a prevalência de DAP em uma população brasileira de portadores de HF. Estudamos também sua associação com diversos fatores de risco cardiovascular, incluindo sexo, idade, hipertensão arterial sistêmica, diabetes mellitus, tabagismo, perfil lipídico, níveis séricos de glicemia e creatinina. Avaliou-se também a associação da DAP com histórico prévio de doença cardiovascular (DCV) bem como sua associação com marcadores de aterosclerose subclínica representados pela angiotomografia coronariana e escore de cálcio coronário. Foram estudados 212 portadores de HF, sendo que em 86% foi comprovada presença de mutação do receptor da LDL e um grupo de comparação composto por 524 indivíduos normolipidêmicos. O rastreamento da DAP foi realizado por dois avaliadores treinados, pela medida do índice tornozelo-braquial (ITB) avaliado em repouso na posição supina, com Doppler vascular portátil. Houve maior prevalência de DAP definida por ITB <= 0,90 em portadores de HF comparados aos controles (17,5% vs. 2,3%, respectivamente; p < 0,001). As variáveis que se associaram independentemente com a alteração dos valores do ITB nos grupos estudados foram, a idade, antecedente prévio de doença cardiovascular e o indivíduo ser portador de HF (OR= 5,77 IC 95% 2,83-11,77, p < 0,001). Na população de HF as variáveis que se associaram independentemente à alteração dos valores de ITB foram a idade e a presença de histórico de tabagismo ativo ou passado. Houve uma associação univariada entre o histórico de doença cardiovascular e o diagnóstico de doença arterial periférica nesta população (OR= 3,20 IC 95% 1,53-6,67, p=0,001), porém tal associação não se manteve significativa quando ajustada por variáveis de confusão. Da mesma forma não se encontrou associação entre os valores alterados de ITB e a presença de placa coronariana e sua gravidade, bem como com o escore de cálcio coronário. Os dados sugerem dissociação entre o desenvolvimento da aterosclerose em diferentes leitos arteriais .Em conclusão, nossos resultados indicam que a DAP é mais frequente na HF do que em indivíduos normolipidêmicos e que outros fatores de risco potencializam o colesterol para sua presença. Não foi encontrada associação independente da alteração do ITB com manifestação de DCV prévia e com a aterosclerose coronária subclínica. Contudo, mais estudos são necessários para determinar o papel do uso do ITB como ferramenta para avaliação do risco de eventos cardiovasculares nessa população / Familial hypercholesterolemia (FH) is a genetic disease of autosomal dominant inheritance characterized by elevated serum levels of total and low density lipoprotein ( LDL - c ) cholesterol. FH is associated to atherosclerosis and can determine the early development of obstructive lesions in different arterial beds. In this context, FH has also been proposed as a risk factor for peripheral arterial disease (PAD). In a cross-sectional observational study the prevalence of PAD in a Brazilian population of patients with FH was determined . We also study its association with several cardiovascular risk factors, including gender, age , hypertension , diabetes mellitus , smoking , lipid profile , serum glucose and creatinine. The association of PAD with previous manifestations of cardiovascular disease (CVD) and with markers of subclinical coronary atherosclerosis detected by computed tomography coronary angiography and coronary calcium score was also evaluated. We studied 212 patients with FH, of which 86% had a confirmed diagnosis by the presence of LDL receptor mutations, and a comparison group consisting of 524 normolipidemic subjects . PAD diagnosis was made by 2 trained evaluators, by the ankle-brachial index ( ABI ) measured at rest in the supine position. There was a higher prevalence of PAD defined as ABI <= 0.90 in patients with HF compared with controls (17.5 % vs . 2.3% , p < 0.001 ) . The variables that were independently associated with altered ABI values in both groups were age, previous history of CVD and the diagnosis of FH (OR = 5.77 95% CI 2.83 to 11.77 , p < 0.001). In FH subjects variables independently associated with altered ABI values were age and the presence of current or past smoking history. There was a univariate association between CVD history and the diagnosis of PAD in this population (OR = 3.20 95% CI 1.53 to 6.67 , p = 0.001), but this association did not remain significant when adjusted for confounders . Likewise, no association was found between the values of altered ABI and the presence of coronary plaque and its severity, as well with the coronary calcium score. The data suggest that there is a dissociation of atherosclerosis development in different arterial beds. In conclusion, our results indicate that PAD is more common in FH than in normolipidemic subjects and that other risk factors potentiate cholesterol to determine its presence. No independent association was found between the alteration of ABI values with manifestations of prior CVD, as well as with the presence of subclinical coronary atherosclerosis. More studies are needed to determine the role of ABI use as a tool for assessing the risk of cardiovascular events in FH

Dans la perspective d’une contribution à l’histoire de l’Aquitaine, l’étude s’attache à définir un cadre spatial suffisamment représentatif – à savoir la vallée du Lot de Fumel à la confluence avec la Garonne. Le fait d’adjoindre à notre recherche, la zone de la confluence, place automatiquement notre étude dans la dépendance de l’axe garonnais, et du débouché en aval que constitue la ville portuaire de Bordeaux, dont on sait l’extraordinaire dynamisme au XVIIIe siècle. Quelles sont les stratégies de nos quatre communautés face au pôle d’attraction bordelais qui impulse, à la descente comme à la remonte, un trafic commercial largement tributaire des besoins d’une ville en pleine expansion et du commerce avec les îles. La matière constitutive de cette histoire sociale s’appuie sur le traitement quantitatif des contrats de mariages et inventaires après décès, ces derniers en nombres plus limités. Une première évaluation du corpus disponible pour les quatre localités citées et inventorié aux Archives du Lot-et-Garonne, dépasse les cinq mille documents. L’exploitation exhaustive de ces sources s’ordonne sur trois périodes de dix ou vingt ans voisinant les limites du XVIIIe siècle et une période en son milieu. Les données issues de notre enquête doivent permettre l’élaboration d’une stratigraphie sociale, témoignage significatif de la vocation particulière de chacune des localités. L’approche comparative sur la durée séculaire renforce cette perception en l’inscrivant dans une dynamique évolutive sur le long terme. Nous envisageons ainsi une lecture plus en profondeur, au plus près de l’individu, comme nous y invite le courant actuel de la réflexion historiographique autour des comportements. Ascension sociale et déclassement seront-ils lisibles comme autant de stratégies volontaires ou de reproduction d’un modèle fondé sur et dans sa catégorie d’appartenance, largement relayé par l’univers familial? / From the perspective of a contribution to the history of Aquitaine, the study will seek to set a sufficiently representative spatial framework - i.e. the Valley of the Lot to Fumel at the confluence with the River Garonne. The fact to add to our research, the area of the confluence place automatically our study in the dependence of the garonnais axis, and outlet downstream that is the port city of Bordeaux, is known to the extraordinary dynamism in the 18th century. What are the strategies of our four communities facing the Centre of Bordeaux attraction that impulse to the descent as to the dates, commercial traffic largely dependent on the needs of a growing city and trade with the Islands. The constituent material of this social history is based on the quantitative treatment of inventories after deaths and marriages contracts, these more limited; a first evaluation of the corpus available for the four localities cited, and inventoried in the Archives of Lot-et-Garonne, close to five thousand documents. The comprehensive exploitation of these sources is arranged on three periods of ten or twenty years surrounding the limits of the eighteenth century and a period in the middle. Our survey data should allow the development of a social stratigraphy, significant testimony of the particular vocation of each of the localities. The comparative approach to the age-old duration will strengthen this perception by placing it in an evolutionary dynamics in the long term. We also consider a reading more in depth, closer to the individual, as we invite the current historiographical reflection around behaviors. Will social ascent and decommissioning be readable as a voluntary strategies or reproduction of a model based on and in its category of membership, widely reported by the family universe?

L’hypercholestérolémie familiale à transmission autosomique dominante (ADH), caractérisée par une élévation des taux plasmatiques en cholestérol total et LDL-C, est due à des altérations de 4 gènes : LDLR, APOB, PCSK9 et APOE. L’objectif principal de cette thèse est d’identifier de nouveaux gènes impliqués dans l’ADH. L’identification de nouveaux gènes sera suivie de l’étude des mécanismes physiopathologiques liés à leurs mutations. Un deuxième objectif est de calculer le score génétique (GRS) chez tous les individus appartenant à 5 familles où une mutation FH a déjà été identifiée afin de déterminer si une forme polygénique expliquerait les cas de phénocopies observés. Parallèlement, nous avons mené une étude dans la population libanaise caractérisée par une fréquence élevée de dyslipidémie et qui représente un outil d’étude remarquable au plan génétique du fait de l’existence d’une forte homogénéité du fond génétique.Ce projet de recherche a permis de révéler un gène candidat pouvant être impliqué dans l’ADH : LRP6. De plus il a permis de remettre en question le rôle du récepteur LRP6 jusqu’à présent considéré comme un protagoniste important dans l’internalisation des LDL. Des études supplémentaires sont encore nécessaires afin de confirmer ou non l’implication de ce gène dans l’ADH et de déterminer son rôle exact dans le métabolisme du cholestérol. Concernant le score polygénique, nous avons montré que le GRS ne peut pas être considéré comme un outil de diagnostic pour différencier les sujets avec une hypercholestérolémie monogénique de ceux avec une hypercholestérolémie polygénique et ne peut pas être utilisé pour expliquer les cas de phénocopies / Atherosclerosis and its cardiovascular complications are the leading causes of morbidity and mortality in industrialized countries. Hypercholesterolemia is one of the major cardiovascular risk factors and it affects one in 20 subjects in the general population. Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma total cholesterol and LDL-C levels, is due to alterations in 4 genes: LDLR, APOB, PCSK9 and APOE. The fundamental work of Brown and Goldstein revealed the important role of the mutations in the LDLR gene in ADH and contributed to the development of a major class of cholesterol-lowering drugs: statins. Similarly, the discovery by Abifadel et al. in 2003 of the first hypercholesterolemic mutations of PCSK9 was the starting point of an adventure which resulted, 12 years later, in the development of a new class of cholesterol-lowering drugs: anti-PCSK9 antibodies. The main objective of this thesis is to discover new genes, major genetic factors and modifiers involved in ADH. The identification of new genes will be followed by the study of the pathophysiological mechanisms linked to their mutations. A second objective of this work is to calculate the genetic risk score (GRS) in all individuals belonging to 5 families where a mutation responsible of the hypercholesterolemic phenotype has been already identified in order to determine whether a polygenic form would explain the phenocopies observed in these families. In parallel to these two projects, we conducted a study in the Lebanese population which is characterized by a high incidence of dyslipidemia. In this population, it is interesting to conduct genetic studies because of the existence of a limited number of sub-populations that constitute "genetic isolates" with a high homogeneity of their genetic background, making it easier to study many hereditary diseases such as familial hypercholesterolemia. The results obtained in this project revealed a candidate gene that could be involved in ADH: LRP6. Moreover, it allowed us to question about the exact role of the LRP6 receptor until now considered as an important protagonist in the internalization of LDL particles. Further studies are still needed to confirm whether or not this gene is involved in ADH and to determine its exact role in cholesterol metabolism. Concerning the genetic score, we have shown that the GRS does not seem to be a reliable diagnostic tool to identify polygenic hypercholesterolemia at the individual level. The 6-SNP score did not give us a clear answer and thus we cannot use the GRS to identify phenocopies within ADH families

Conditions related to tobacco use constitute the single most preventable cause of death in the United States. Approximately 443,000 U.S. adults die each year from smoking-related illnesses. During young adulthood, social and behavioral changes occur; experimentation with tobacco products such as cigarettes is common and may lead to a habit of smoking. A gap was identified in the literature on the perceived impact of family communication on young adults' decisions regarding smoking. The purpose of this descriptive phenomenological study was to address this gap by gathering information on the perspectives of young adults toward tobacco use. Fifteen young adults aged 18 to 26 from the northeastern region of New Jersey who were currently engaged in the use of tobacco products participated in open-ended interviews. Research questions were designed to investigate young adults' views and perceptions regarding cigarette use and to explore information regarding how smoking-related communication received from family members influenced young adults' decision to smoke. The theory of planned behavior and social learning theory provided the theoretical underpinnings and consistent themes by young adults from the study. Van Manen's data analysis strategy demonstrated thematic reports from young adults that behaviors, habits, attitudes, communications, including verbal and nonverbal cues and practices are learned from their parental figures in the home environment. Recommendations for future research include exploring young adults from other geographical locations regarding their perspectives toward tobacco use. This study may promote positive social change for the public and health practitioners by providing insight on family interactions regarding smoking behaviors for young adults..

Notre système juridique laisse apparaître un déséquilibre entre droits et devoirs qui place le créancier dans une situation inconfortable face à un débiteur de mauvaise foi. L’ampleur de la crise économique mondiale, qui persiste depuis près d’une décennie, a institué un climat d’incertitude. Le manquement à l’obligation d’exécution des contrats en est une des conséquences principales, notamment l’inexécution du débiteur envers son créancier. De ce fait, le règlement est devenu la préoccupation majeure. Certes, l’inexécution est condamnée par le législateur, dans le but de conserver un équilibre entre les parties au contrat. Toutefois, malgré les nombreuses et fructueuses évolutions, une observation plus minutieuse de la situation fait émerger une surprotection sous-jacente du débiteur qui s’est vu octroyer de nombreux privilèges. A contrario, la place du créancier présente des signes d’affaiblissement dans notre système juridique et fonctionnement économique. Cette situation est préoccupante, dans la mesure où elle induit un ralentissement de l’économie nationale, dû à une fuite avérée des investissements en dehors de notre territoire, au profit d’autres pays européens. Cet état de fait se présente comme un problème subjectif mais également objectif, et il est nécessaire d’étudier les divers obstacles qui se dressent devant le créancier lors de la procédure de saisie du logement familial du débiteur. Le terme « obstacles » renvoie aux contraintes que le créancier doit prendre en compte, en amont mais aussi tout au long de la procédure de saisie, qui l’empêchent de recouvrer sa créance et par conséquent de réinvestir. Il est donc essentiel de proposer des solutions afin de répondre à un besoin de rééquilibrage des forces en présence, dans un contexte économique dégradé, qui suppose une adaptation du cadre législatif. / Our legal system in France reveals a discrepancy between rights and obligations whereby the creditor is plunged into a much more critical situation as compared to the bad faith debtor. The magnitude of the economic crisis that has lasted for more than a decade has causes a climate of considerable uncertainty. The failure to comply with the obligation of execution of contracts proves to be one of the main consequences, particularly the violation of the debtor’s duty to the creditor. Therefore regulations, in which lawmakers condemn the failure to meet contracts in order to secure a balance between parties, have become the main issue. However, despite a drastic and positive evolution in our legal system it appears when following the situatio more carefully that the debtor was in fact granted with numerous privileges. In fact, in our current legal system and economic situation the creditor’s position shows signs of weakening. This is an issue of concern. Investments are thus moving abroad, benefiting other European member states and resulting in a dip in our own national economy. As this is an eestablished fact, it is necessary to consider the various main obstacles in the legal framework, which the creditor has to overcome. One example is the case of a debtor’s family property seizure. The term « obstacles »refers to the contraint satisfaction process, before and during the seizure procedure, preventing the creditor from recovering her/his outstanding debt. As a matter of fact, the lasting unfavorable economic situation supposes to consider solutions in order to better balance forces, including changes in the legal framework.

Lorsqu'on cherche à situer politiquement les femmes, dans la première moitié du XIXème siècle, la réponse semble aujourd'hui s'imposer d'elle-même : privées du droit de suffrage, elles sont exclues de la citoyenneté révolutionnaire, universelle et individualiste telle qu'elle est définie à partir de 1789. Le constat de leur exclusion, d'une objectivité irréprochable, ne rend pourtant pas compte de leur situation politique, telle qu'elle est pensée, du moins, à cette époque (de 1789 à 1848). Peu d'historiens ou de politologues se sont penchés sur la façon dont le cens électoral de l'électeur était calculé : tout se passe comme s'il était payé individuellement, c'est-à-dire sur la base des seules propriétés du citoyen considéré. Or, non seulement le citoyen, s'il est marié, paye les contributions au nom de la communauté de biens qu'il forme avec son épouse ; mais il peut également, selon les lois électorales de l'an X à 1831 incluses, se faire adjoindre les contributions d'autres membres de la famille, fussent-ils eux-mêmes majeurs et de sexe masculin. Le fait que la famille soit, pendant toute cette période, pensée comme une unité politique conduit à reconsidérer la situation des personnes, qui ne peut plus être saisie à travers une approche univoque, en termes de “ qui vote ” et “ qui ne vote pas ”. C'est en tant que membres de la famille que les femmes restent en dehors de la participation politique ; de même que c'est en tant que pater familias que le citoyen est investi du droit individuel de voter au nom de la Nation tout entière. Seul un travail sur les catégories implicites de la construction politique pouvait faire émerger ce qu'on a appelé une conception familialiste du suffrage, caractéristique de toute la période révolutionnaire (1789-1848). C'est ainsi qu'au-delà de la résolution du soi-disant “ problème ” de l'exclusion des femmes, se trouve également modifiée notre conception actuelle de l'individu politique révolutionnaire, plus évolutive qu'on ne le croit.

L'Amazonie brésilienne, qui détient une grand epartie de la biodiversité de la planète, subit actuellement de grandes transformations sur les plans économiques, sociaux, culturels et écologiques. La région Transamazonienne est caractéristique, par l'importance de l'agriculture familiale, en termes d'occupation des surfaces agricoles, population et production d'aliments. Elel se distingue par des systèmes de production agricole diversifiés, où l'élevage laitier joue assume un rôle stratégique pour l'alimentation des familles, et les revenus monétaires obtenus par la vente du lait et des veaux. Dans ce contexte, ces systèmes d'élevage laitiers sont eux-aussi l'objet de transformations, ansi que la filière laitière. L'objectif de cet étude est de comprendre comment fonctionnent ces systèmes laitiers des exploitations agricoles familiales dans une région de front pionnier amazonien, à Brasil Novo (Pará). Un ensemble de méthodologies à été utilisé, combinant des enquêtes auprès d'éleveurs et d'informateurs clés, des analyses rétrospectives sur le rôle du lait dans les rajectoires des exploitations, des typologies d'exploitations en 2001 et en 2009, et une connaissance empirique accumulée par l'auteur au cours de 15 ans de recherche développement dans la région. Les résultats montrent un gradient d'évolution des établissements laitiers, où se détachent deux types de producteurs laitiers, que nous avons nommés " opportunistes " et " persistants ". En fonction d efacteurs internes et externes aux exploitations, se produisent des évolutions constantes des systèmes laitiers aulong de ce gradient. Parmi ces facteurs, l'accès au marché a un rôle central, et définit en grand epartie les orientations que le sproducteurs suivent dans la conduite de leurs systèmes laitiers. La filière du lait apparaît fragilisée. La vente directe du lait du producteur au consommateur é uma pratique encore commune. Les laiteries existentes sont de petites tailles, possèdent un faible rayon de collecte et leur historique de fonctionnement est marqué par une grande instabilité. La précarité des infrastructures, de la mailel routière et d el'électrification sont les principaux facteurs explicatifs de cette faible structuration de la filière. Ces aspects placent les agriculteurs dans des situations de grande incertitude, empêchant des investissements dans l'activité laitière, malgré les bas coûts de production du lait. Ces carences pourraient être résolues par des politique spubliques adaptées, ou par la forte croissance du marchéconsommateur local, que provoquerait l'ouverture de l'usine de Belo Monte.