Familial Hypercholesterolemia: clinical, genetic and metabolomic approaches for diagnostics and research

This PhD project provides insights into the genetic variability within a group of patients with a dyslipidaemic profile, in particular with a clinical diagnosis of possible/probable/certain familial hypercholesterolemia (FH) according to the Dutch Lipid Clinic Network (DLCN) score, characterized by very high LDL-C levels and an increased cardiovascular risk compared to the general population. Data obtained allowed us to confirm the significant role of pathogenic variants in the LDLR gene, the gene most commonly associated with this condition, in determining the patient's clinical phenotype, while the genes APOB, PCSK9, and LDLRAP1 showed a minor role. It was also possible to observe that the presence of additional rare variants, in conjunction with variants in LDLR, may contribute to modulating the phenotype, both in terms of LDL-C concentration and the manifestation of events. In those individuals without variants in LDLR, an important impact on the phenotype is given by the presence of a cumulative burden of polymorphic variants, such as those measured by the Talmud score, which together have an additive effect on increasing LDL-C levels that can reach values comparable to those observed in patients with confirmed FH, causing a polygenic hypercholesterolemia.