Genetic mapping of metabolic biomarkers of cardiometabolic diseases

Cardiometabolic disorders (CMDs) are a major public health problem worldwide. The main goal of this thesis is to characterize the genetic architecture of CMD-related metabolites in a Lebanese cohort. In order to maximise the extraction of meaningful biological information from this dataset, an important part of this thesis focuses on the evaluation and subsequent improvement of the standard methods currently used for molecular epidemiology studies. First, I describe MetaboSignal, a novel network-based approach to explore the genetic regulation of the metabolome. Second, I comprehensively compare the recovery of metabolic information in the different 1H NMR strategies routinely used for metabolic profiling of plasma (standard 1D, spin-echo and JRES). Third, I describe a new method for dimensionality reduction of 1H NMR datasets prior to statistical modelling. Finally, I use all this methodological knowledge to search for molecular biomarkers of CMDs in a Lebanese population. Metabolome-wide association analyses identified a number of metabolites associated with CMDs, as well as several associations involving N-glycan units from acute-phase glycoproteins. Genetic mapping of these metabolites validated previously reported gene-metabolite associations, and revealed two novel loci associated with CMD-related metabolites. Collectively, this work contributes to the ongoing efforts to characterize the molecular mechanisms underlying complex human diseases.Open Acces

Tracking the Temporal-Evolution of Supernova Bubbles in Numerical Simulations

The study of low-dimensional, noisy manifolds embedded in a higher dimensional space has been extremely useful in many applications, from the chemical analysis of multi-phase flows to simulations of galactic mergers. Building a probabilistic model of the manifolds has helped in describing their essential properties and how they vary in space. However, when the manifold is evolving through time, a joint spatio-temporal modelling is needed, in order to fully comprehend its nature. We propose a first-order Markovian process that propagates the spatial probabilistic model of a manifold at fixed time, to its adjacent temporal stages. The proposed methodology is demonstrated using a particle simulation of an interacting dwarf galaxy to describe the evolution of a cavity generated by a Supernov

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes