archives@tulane.edu / Background: Human Biological Aging (BA) estimates are developed by human to better capture the gradual increase in the vulnerability of the aging body than chronological age. Human sleep dimensions have been suggested to be associated with human health indicators including cardiometabolic function, cognitive function and mortality. The objective of this study was to examine indicators of BA and their predictive validity using Klemera and Doubal’s Method (KDM), and Physiological Dysregulation Method (PDM) for quantifying BA, as well as to explore if phenotypical and genetic associations between sleep variables and BA estimates exist, using the Bogalusa Heart Study (BHS) – a community-based, cohort study. Method: In order to estimate BA, nineteen biomarkers were selected. Training datasets were from NHANES. The target dataset included 1,034 BHS subjects assessed between 2013-2016. Training was done separately for male and female, black and white participants. KDM and Mahalanobis Distance (DM) based PDM methods were used. Cognitive and physical performance testing were used to examine predictive validity. The association between three sleep dimension variables and BA estimates were explored using 953 black and white BHS 2013-2016 subjects. Sleep duration in hours, chronotype scores and social jetlag in hours were the independent variables. BA estimates were the dependent variables. Genotyping information from the BHS 2013-2016 were included (n=646) for genetic association. Related SNPs on morning chronotype were used to compute a genetic risk score (GRS) for BHS participants. Association between chronotype GRS and chronotype phenotype were explored. Multivariate linear regression was used for all association analyses. Results: BA estimates were calculated using both the KDM and PDM methods. Linear regression showed that PDM BA estimates were associated with lower cognitive function physical performance tests. The effect sizes of all associations between PDM BA estimates and performance tests were of greater magnitude than between KDM estimates and performance tests. Short sleep duration and evening chronotype was associated with larger PDM BA estimates. Morning chronotype GRS was not associated with morning chronotype phenotype among BHS participants. Conclusion: PDM BA estimates are robust measures of biological aging in black and white men and women enrolled in the BHS. Insufficient sleep duration and evening chronotype may advance biological aging, regardless of gender, race and CA. We did not find association between morning chronotype GRS and morning chronotype phenotype. PDM BA estimates should be recommended for future aging studies using data from BHS participants. / 1 / Xunming Sun

While obesity is a world leading health problem, the most efficient treatment option for severely obese patients is Roux-Y gastric bypass (RYGB) surgery. However, there are large inter-individual differences in weight loss after RYGB surgery. The reasons for this are not yet elucidated and the role of genetics in weight loss-regulation is still not fully understood. The main aim for this thesis was to investigate the effects of common obesity-associated genetic variants and their effect on weight loss and food intake. We examined if the weight loss two years following RYGB surgery depends on the  FTO genotype, as well as pre-surgery vitamin D status. For FTO AA-carriers, the surgery resulted in a 3% per-allele increased excess BMI loss (EBMIL; P=0.02). When split by vitamin D baseline status, the EBMIL of vitamin D deficient patients carrying AA exceeded that of vitamin D deficient patients carrying TT by 14% (P=0.03). No such genotypic differences were found in patients without pre-surgery vitamin D deficiency. As the influence of individual single nucleotide polymorphisms may be small, we identified a novel method to combine SNPs into a genetic risk score (GRS). Using the random forest model, SNPs with high impact on weight loss after RYGB surgery were filtered out. An up to 11% lower EBMIL with higher risk score was estimated for the GRS model (p=0.026) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608 and MAP2K5). Pre-surgical hunger feelings were found to be associated with EBMIL and the SNP rs4846567. Before surgery, patients filled out the Three Factor Eating Questionnaire and were genotyped for known BMI and waist-hip ratio (WHR) associated SNPs. Patients with the lowest hunger scores had up to 32% greater EBMIL compared to the highest scoring patients (P=0.002). TT-allele carriers of rs4846567 showed a 58% lower hunger feelings. TT- carriers also showed a 51% decrease in disinhibition, but no significant impact on cognitive restraint was observed. Due to the association of eating behaviour and weight loss, acute effects on DNA methylation in response to a food intake intervention of a standardized meal were also investigated. After food intake, 1832 CpG sites were differentially methylated compared to the baseline after multiple testing correction. When adjusted for white blood cell fractions, 541 CpG sites remained. This may be interpreted as that the immune system is playing an active role in the response to food intake and highlights the dynamic nature of DNA-methylation. These findings will contribute to a better care for morbidly obese patients. Post-surgical treatment may be optimized so that patients with a less favourable genetic profile may receive additional support for weight loss and weight management. This may be considered as a step in the transition towards personalized medicine.

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

The main expansion of the discovery of genetic variants associated with complex diseases has occurred during the last decade. This expansion has been accompanied, and in some sense motivated, by the desire to use this information to improve the predictive capacity of many diseases with an unidentified familial component, including coronary heart disease (CHD), with the aim of translating this genetic knowledge into clinical practice. This doctoral thesis is structured in two lines of investigation that address distinct aspects of this issue, first to evaluate the possible role of genetic variation in a candidate gene in modulating CHD risk, and second to evaluate whether genetic information can be used to improve risk assessment tools used in clinical practice. In the first research line (described in Part I), we investigate the contribution of genetic variation in one of the most widely-studied genes in cardiovascular genetics, ESR1, which encodes the Oestrogen receptor α protein. We provide a solid meta-analysis of evidence regarding the most widely-studied variant in this gene and we further explore the role of a broad range of common and uncommon variants in this gene in CHD risk. Using these approaches, we find no evidence of association between the genetic variants studied and CHD risk. However, although we can confidently accept that common genetic polymorphisms are not associated with cardiovascular disease, we cannot discard the possibility that other types of variation in this gene (for instance epigenetic variation) could modify susceptibility to cardiovascular disease, or that other elements of this pathway are associated with an increased risk of CHD. In this research I have provided a reliable answer to this long running unanswered question in cardiovascular genetics, allowing research to re-focus on other elements of this system or other pathways. In the second line, we explored the possible utility of genetic information obtained from genome-wide association studies (GWAS) in prediction of 10-year risk of CHD events by adding this information to cardiovascular risk functions. We have followed the recommendations proposed by the American Heart Association for evaluating the utility of novel biomarkers in clinical practice, and have demonstrated that although the magnitudes of the effects of these genetic variants on CHD risk are modest, there is a tendency towards improvement in the capacity of the risk functions to predict future CHD events. The translation of genetic information into clinical practice was one of the main motivations for the investment in genome-wide association studies, and my research represents one of the first efforts to explore this possibility. / L’expansió principal pel que fa al descobriment de variants genètiques associades amb malalties complexes s’ha dut a terme durant la última dècada. Aquesta expansió ha estat acompanyada, i d’alguna forma motivada, pel desig d’usar aquesta informació per millorar la capacitat de predicció d’aquelles malalties on hi és present un cert component familiar però en les que no es coneixien les variants que conferien un major risc de patir la malaltia, entre elles la cardiopatia isquèmica (CI). La present tesis doctoral està estructurada en dues línies d’investigació que avaluen el possible rol d’un gen candidat en la susceptibilitat de la CI i també avalua la millora en la capacitat de predicció d’un esdeveniment coronari de les eines usades habitualment en la pràctica clínica mitjançant la inclusió d’informació genètica. Més concretament, la primera línea d’investigació es centra en la contribució de la variació genètica en un dels gens més estudiats en relació amb CI: el gen que codifica pel receptor d’estrogens alfa (ESR1). En aquesta línea hem proveït un sòlid meta-anàlisis entre la variant més àmpliament estudiada d’aquest gen i risc coronari i també hem explorat el paper de la majoria de les variants comunes descrites en aquest gen i risc de CI. Mitjançant cap dels anàlisis hem trobat evidència d’associació entre les variants genètiques en aquest gen i el risc de CI. No obstant això, i encara que podem acceptar que les variants genètiques comunes d’aquest gen no estan associades amb esdeveniments coronaris, no podem descartar que altres tipus de variació en aquest gen (com per exemple variació epigenètica) pugui estar modificant la susceptibilitat a patir un esdeveniment coronari, ni tampoc que altres elements de la mateixa cadena de senyalització estiguin associats amb la malaltia. En la segona línea d’investigació, hem explorat el possible paper de les variants genètiques, obtingudes mitjançant estudis d’associació global del genoma (GWAS), en la millora de la capacitat de predicció a 10 anys dels esdeveniments coronaris, mitjançant la seva addició en les funcions de risc cardiovascular clàssiques. Hem seguit les recomanacions proposades per la American Heart Association per l’avaluació en la pràctica clínica de nous biomarcadors, i hem demostrat que, tot i que la magnitud de l’associació d’aquestes variants és modesta, hi ha una tendència cap a la millora de la capacitat de predicció de les funcions de risc.

No description available.

Les maladies complexes telles que les maladies cardio-Vasculaires (MCV) sont influencées par des facteurs génétiques et environnementaux. L’estimation du risque cardio-Vasculaire chez un individu est généralement évaluée par la sommation des facteurs de risque reconnu des MCV (p. ex. l’âge, le sexe, le tabac, la pression artérielle et le cholestérol). Dernièrement, plusieurs bio-Marqueurs ont été examiné pour leur aptitude à améliorer la prédiction des maladies cardio-Vasculaires au-Delà des facteurs de risques traditionnels. L’intérêt de découvrir de nouveaux loci est incité notamment par les découvertes qui émergent des études d'association pangénomique (GWAS) qui permettent de tester l’association de variation génétique au risque de contracter une maladie commune. Les GWAS ont considérablement amélioré notre connaissance de l'architecture génétique des maladies cardio-Vasculaires, à ce jour plus de 50 variations génétiques sont formellement associées à des maladies cardio-Vasculaires, de même plus de 200 marqueurs génétiques seraient associés à des facteurs de risque cardiovasculaire traditionnels (p. ex. le taux sanguin des lipides, la pression artérielle, l’indice de masse corporelle et le diabète de type 2). Le succès remarquable de ces études d’association, qui a permis l’identification de nombreux bio-Marqueurs, a conduit à une réévaluation des données génétiques dans le but de définir des informations cliniquement utiles pour limiter et mieux prédire les risques de maladies, grâce à une application plus efficace des stratégies de prévention. Dans cette thèse, nous examinons tout d'abord une nouvelle approche pour étudier l'architecture génétique de l'hypertension artérielle (HTA; facteur de risque majeur des maladies cardiovasculaires prématurées), puis nous avons constitué plusieurs modèles pour prédire le risque de développer une maladie coronarienne (MC; type le plus commun de MCV), enfin nous avons déterminé une base génétique commune du principal prédicteur de complications cliniques des maladies coronariennes – l'athérosclérose subclinique - afin d'ajouter une valeur pronostique supplémentaire en plus des scores de risque traditionnels à différents âges. Nous avons estimé l'héritabilité de la première mesure de la pression artérielle systolique (PAS) à ~25%/~45% et à ~30%/~37% pour la pression artérielle diastolique (PAD) chez les sujets d’origine Européenne (N = 8901) et d’origine Africaine (N = 2860) faisant respectivement partie de la cohorte Atherosclerosis Risk in Communities (ARIC), en accord avec les études antérieures. Par ailleurs, nous avons développé un moyen de combiner un score de risque génétique (SRC) – somme des effets génétiques parmi un ensemble de marqueurs – avec une évaluation indépendante du risque clinique, en utilisant un système d'équations log-Linéaire. Nous avons employé cet outil à la prédiction de la maladie coronarienne (MC) dans la cohorte ARIC. L'ajout d'un score de risque génétique (SRG) à un score de risque clinique (SRC) améliore à la fois la discrimination et l'étalonnage des maladies coronariennes dans la cohorte ARIC, et révèle par la même comment cette information génétique influence l'évaluation des risques ainsi que l’approche clinique. Enfin, parmi 1561 cas et 5068 contrôles (de la présence ou non de calcifications coronaires), faisant partie de plusieurs ensembles de données cliniques et génétiques disponibles via la base de données NCBI de Génotypes et Phénotypes (dbGAP), nous avons constaté qu’une augmentation d'un écart-Type dans le score de risque génétique de 49 bio-Marqueurs de MC est associée à 28 % d’augmentation de risque de développer une athérosclérose coronarienne subclinique diagnostiquée à un stade avancé (p=1.43x10-16). Cette augmentation du risque est significative dans chaque catégorie d'âge (de 15 ans en 15 ans) (0,01 > p > 9.4x10-7) et a été remarquablement similaire dans toutes les catégories d'âge (test d'hétérogénéité p = 0.98). (...) / Complex diseases such as cardiovascular disease (CVD) are influenced by both genetic and environmental factors. Estimation of an individual’s cardiovascular risk usually involves measurement of risk factors correlated with risk of CVD (e.g. age, sex, smoking, blood pressure, and total cholesterol). Lately, several biomarkers have been evaluated for their ability to improve prediction of cardiovascular disease beyond traditional risk factors. The interest in novel loci is propelled notably by emerging discoveries from the advent of genome-Wide association studies (GWAS) of genetic variants associated with risk for common diseases. GWAS has greatly enhanced our knowledge of the genetic architecture of cardiovascular disease, yielding over 50 variants confirmed to be associated with CVD to date, as well as over 200 associated with traditional cardiovascular risk factors (e.g. lipids, blood pressure, body mass index, and type 2 diabetes mellitus). This recent and continuing success in discovering increasing numbers of robustly associated genetic markers has led to reassessment of whether genetic data can provide clinically useful information by refining risk prediction and moderating disease risk through a more efficient application of prevention strategies. In this thesis, we first address novel approach to survey the genetic architecture of hypertension (i.e. major risk factor for premature CVD), then construct risk prediction models for coronary artery disease (CAD; i.e. most common type of CVD) and finally establish a common genetic basis of the strongest predictor of clinical complications of CAD, subclinical atherosclerosis, to add incremental prognostic value above traditional risk scores across a range of ages. We show that, for first visit measurements, the heritability is ~25%/~45% and ~30%/~37% for systolic (SBP) and diastolic blood pressure (DBP) in European (N=8,901) and African (N=2,860) ancestry individuals from the Atherosclerosis Risk in Communities (ARIC) cohort, respectively, in accord with prior studies. Then we present a means to combine a polygenic risk score - genetic effects among an ensemble of markers - with an independent assessment of clinical risk using a log-Link function. We apply the method to the prediction of coronary heart disease (CHD) in the ARIC cohort. The addition of a genetic risk score (GRS) to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC and subsequently reveal how this genetic information influences risk assessment and thus potentially clinical management. Finally, Among 1561 cases and 5068 controls, from several clinical and genetic datasets available through the NCBI's database of Genotypes and Phenotypes (dbGAP), we found a one SD increase in the genetic risk score of 49 CAD SNPs was associated with a 28% increased risk of having advanced subclinical coronary atherosclerosis (p = 1.43 x 10-16). This increase in risk was significant in every 15-Year age stratum (.01 > p > 9.4 x 10-7) and was remarkably similar across all age strata (p test of heterogeneity = 0.98). We obtained near identical results and levels of significance when we restricted the genetic risk score to 32 SNPs not associated with traditional risk factors. Accordingly, common variation largely recapitulates the known heritability of blood pressure traits. The vast majority of this heritability varies by chromosome, depending on its length, and is largely concentrated in intronic and intergenic regions of the genome but widely distributed across the common allele frequency spectrum. Respectively, our proposed method to combine genetic information at established susceptibility loci with a nongenetic risk prediction tool facilitates the standardized incorporation of a GRS in risk assessment. (...)