DPSPDNT - Teses de doutoramento
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- Tackling the molecular basis of lipid metabolism: from candidate genes testing in a disease cohort to multi-omics approaches in unselected populationsPublication . Rossi, Niccolò; Bourbon, Mafalda; Falchi, MárioDyslipidemia, broadly defined as an unhealthy deviation of plasma lipid levels, is a well-known heritable risk factor for c ardiovascular diseases (CVD), the first cause of death worldwide. Uncovering the genetic basis of p lasma lipids is, therefore, fundamental for CVD prevention and treatment. In this work, I tackled dyslipidemia from two different perspectives, namely genetics of severe dyslipidemia in a disease cohort and multi-omics of plasma lipids variation in unselected populations. First, I aimed to investigate if mutations in genes involved in miscellaneous monogenic dyslipidemia can mimic a Familial Hypercholesterolemia-like phenotype. By knocking-down dyslipidemia genes in cultured cells, I observed that sitosterolemia and hypertriglyceridemia causing genes are negative regulators o f LDL-uptake in vitro. Targeted sequencing of 1 85 FH mutation-negative individuals from the Portuguese FH study and subsequent cascade family screening for c andidate pathogenic variants, highlighted nine variants in ABCG5, ABCG8 and GPD1 co-segregating with the FH-phenotype. Mutations in these three genes, in heterozygosity, were associated with increased plasma LDL-cholesterol (LDL-C) as compared to the normal population (β = +71.38±9.57, +76.11±10.14 and +65.96±8.77 mg/dL, respectively). Rare genetic variants underlying extreme dyslipidemia tend to be conserved across ethnic groups. Instead, the study of rare variations underlying non-monogenic dyslipidemia in multi-ethnic populations remains challenging. Here, I looked for rare single nucleotide variants, individually or in aggregate, associated with plasma LDL-C from whole-genome sequencing data in 1,751 participants f rom the TwinsUK c ohort and replicated my findings in 2,587 individuals from the Qatar Genome Programme. I identified a conserved locus located upstream the KCNJ2 gene associated with LDL-C levels, at both single and aggregate variants levels in the two cohorts, and with myocardial infarction risk in TwinsUK. Loci identified by association studies have the potential to reveal novel genes and pathways involved in dyslipidemia biology. However, individual genes do not work alone, but rather interact with one another and jointly affect human health. I constructed gene co-expression networks based on RNA sequencing data generated from subcutaneous adipose and skin tissues, and lymphoblastoid cell lines from 856 subjects from the TwinsUK cohort. First, by testing the enrichment of co-expression modules for l ipid-related gene ontologies and GWAS hits, I defined a lipid functional gene module. Within this module, the expression level of the long non-coding RNA LINC00263 and transcription factor Srebf1, a key player in adipogenesis, were found to be highly correlated (Pearson’s ρ = 0.62; P = 3.71x10 -81) . In addition, I observed that LINC00263 predicted interactors are specifically expressed in adipocytes and are enriched for lipid-related pathways. Thus, I propose LINC00263 as a novel candidate lipid regulator in subcutaneous adipose tissue. Together, the results presented in this thesis provide new insights into dyslipidemia complex aetiology both at the genomic and transcriptomic level, and improve CVD risk assessment and prevention.