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Browsing DPSPDNT - Teses de doutoramento by Author "Costa, Cibelle Neiva Cavalcanti Mariano da"
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- Biochemical and molecular characterisation of the dyslipidaemia in PortugalPublication . Costa, Cibelle Neiva Cavalcanti Mariano da; Bourbon, Mafalda; Antunes, MaríliaABSTRACT: Dyslipidaemia is one of the major modifiable independent risk factors for cardiovascular disease (CVD), with both genetic and environmental determinants. Although genetic risk factors are considered as non-modifiable, their CVD-associated risk can be prevented if early identified. The correct and early identification of dyslipidaemia is important for a better patient management and could definitely contribute to CVD prevention. This thesis intended the most complete characterisation of the dyslipidaemia in the Portuguese population, both biochemically and molecularly. Reference values based on population-specific percentiles for lipid and lipoprotein biomarkers were provided for the first time in the Portuguese population, namely total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (apoA1), apolipoprotein B (apoB), small, dense LDL-C (sdLDL-C), lipoprotein(a) [Lp(a)], as well apoB/apoA1 and sdLDL-C/LDL-C ratios, and non-HDL-C and remnant cholesterol. To our knowledge, the sdLDL-C percentiles were the first to be established in an European population. The percentiles were estimated through a rigorous methodology and compared with other population percentiles by a very visual and feasible method, showing relevant differences. These newly determined reference values for lipid biomarkers were then used to characterise the dyslipidaemia in our population, and can now be used in the clinic for a better patient care and management. More than cholesterol per se, our study highlighted apoB and sdLDL-C as important biomarkers to be used in dyslipidaemia evaluation. Individuals presenting extreme phenotypes were further investigated to assess possible monogenic causes, and three individuals were found to have familial hypercholesterolemia (FH), the most common genetic dyslipidaemia and one of the most common disorders that confer an increased cardiovascular risk. Finally, in an attempt to explore the causes for the FH phenotype, a polygenic risk score was validated for the first time in the Portuguese population. A total of 289 index cases were identified with monogenic FH and other causes for their dyslipidaemia, and also 100 were identified with polygenic hypercholesterolaemia, representing 53.21% of the cohort. From the monogenic causes, 91.35% have a mutation in LDLR, 4.84% in APOB, 1.04% in PCSK9 and 2.08% had mutations in phenocopies genes (LIPA, APOE, ALB), suggesting that all those monogenic and polygenic causes should be always investigated for a better patient identification. This study provided the most complete characterisation of the dyslipidaemia in the Portuguese population, and important evidences for dyslipidaemia evaluation has been produced. The results obtained have application, not only for Portugal or a south European populations, but also might have an worldwide utility for the dyslipidaemia assessment. Together, the results obtained provide useful information on an important cardiovascular risk factor and should help to tackle and identify at risk situations that need urgent measures.