GENETIC DYSLIPIDAEMIAS IN THE ITALIAN AND RUSSIAN POPULATIONS:FROM THE CLINIC TO THE BENCH

Genetic dyslipidemias are a heterogeneous group of disorders, and familial hypercholesterolemia (FH) is the most common one, that are characterized by abnormal levels of circulating lipoproteins and leading to premature cardiovascular diseases (CVD). Despite the need for an accurate and timely diagnosis due to high cardiovascular risk of those patients - there is still no well-managed system for a diagnosis and treatment of patients with severe dyslipidemias, - there are still some gaps between clinical and genetic diagnosis scores that need to be improved to increase their reliability at the population level. To overcome the above mentioned challenges, national registries on lipid disorders have been created as a tool to improve a screening programs and to make a progress towards formulating a joint consensus on methods to improve accuracy of its diagnosis and cardiovascular risk stratification. The Italian and Russian Genetic Network (a background for the current PhD project) has been initiated with the primary focus on familial hypercholesterolemia as a genetically determined lipid disorder with the highest prevalence worldwide. The key goal of the current PhD thesis was to provide a phenotype – genotype characterization of the two populations aiming to use these data for searching of new approaches for improvement of an accuracy of FH diagnostics and cardiovascular risk stratification to promote in a future personalized approach in a disease management. The additional advantage of the current Network is an availability of a two-population validation of potential new markers for FH detection to will allow for an improvement of current algorithms. Thus, we studied two cohorts from north cities of Italy and Russia (Milan and Saint Petersburg), a phenotype – genotype characterization for both cohorts was performed as well as concreate gaps between clinical and genetic diagnosis were described. The ultrasound measurement of Achilles tendon thickness was considered as a potential marker to fill in the gap between clinical and genetic FH diagnosis that brings an additional value to identification of FH subjects with higher LDL-C burden that may affect the level of the aggressiveness for the therapeutic strategies. Furthermore, proteomic data analysis demonstrated that a set of immune-inflammatory proteins associated with increased CVD risk, significantly characterize the clinically determined FH phenotype. Crossing the clinical phenotype with genetic analysis allowed to identify genetically positive FH individuals that, in addition to a higher LDL-C burden, were also characterized by a peculiar set of immune-inflammatory proteins as compared to genetically negative ones. By pairing genetically positive and negative FH patients for LDL-C levels, a number of significantly different proteins was indicated, that let to suggest that the prognostic value of these proteins should be longitudinally addressed. In conclusion, the Italian and Russian Genetic Network contributed to reinforcing of knowledge about FH in both countries within the access to performing and interpretation of genetic results and analysis of approaches for an increase FH detection and risk stratification accuracy to driving improvement in standards of care for FH patients globally.