Lipidomic Signature of Patients with Familial Hypercholesterolemia Carrying Pathogenic Variants Unveils a Cue of Increased Cardiovascular Risk

Familial Hypercholesterolemia (FH) is a common genetic disorder characterized by elevated LDL-cholesterol levels and an increased risk of premature cardiovascular disease. While pathogenic variants in <i>LDLR</i>, <i>APOB</i>, and <i>PCSK9</i> are well-established causes, a substantial proportion of clinically suspected FH cases do not carry either pathogenic variants or rare variants of uncertain significance in these genes (FH/V-/USV-). This study aimed to characterize the metabolome/lipidome of genetically confirmed heterozygous FH (HeFH) patients compared to FH/V-/USV-, seeking to identify specific alterations associated with genetic status and phenotypic variability. Untargeted high-resolution mass spectrometry (UHPLC-Q-Exactive-MS)-based lipidomics and nuclear magnetic resonance-based metabolomics were performed on plasma samples of FH patients (n = 20 HeFH and n = 19 FH/V-/USV-) towards healthy controls (n = 22). PLS-DA analysis revealed group-level separation, suggesting differences in the circulating metabolome/lipidome. As expected, most of identified lipid classes were higher in both FH groups compared to normolipidemic controls. Notably, significant lipids (VIP > 1, <i>p</i> < 0.05) showed potential in distinguishing HeFH and FH/V-/USV- patients, particularly sphingomyelins. These data were confirmed by multivariable regression analysis controlling for age, sex, and lipid-lowering therapy as well as by ROC analysis. The evidence of a distinct lipidome signature in the HeFH subgroup may relate to the increased cardiovascular risk of HeFH patients compared to patients without pathogenic variants.