LAUSR

BACKGROUND AND AIMS Patients with familial hypercholesterolemia (FH) are often characterized by premature coronary artery disease (CAD) with heterogeneity at onset. The aim of the present study was to investigate the associations of lipoprotein (a) [Lp(a)] with the FH phenotype, genotype and roles of Lp(a) in determining CAD risk among patients with and without FH. METHODS We enrolled 8050 patients undergoing coronary angiography, from our Lipid clinic. Clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. Mutational analysis (LDLR, APOB, PCSK9) in definite/probable FH was performed by target exome sequencing. RESULTS Lp(a) levels were increased, with a clinical FH diagnosis (unlikely, possible, definite/probable FH) independent of the patients status, with Lp(a)-hyperlipoproteinemia [Lp(a)-HLP] (median 517.70 vs. 570.98 vs. 604.65 mg/L, p < 0.001) or without (median 89.20 vs. 99.20 vs. 133.67 mg/L, p < 0.001). Patients with Lp(a)-HLP had a higher prevalence of definite/probable FH than those without (6.1% vs. 2.4%, p < 0.05). However, no significant difference in Lp(a) was observed in patients with definite/probable FH phenotype carrying LDLR or LDLR-independent (APOB, PCSK9) or neither mutations (p > 0.05). Multivariate analysis showed that Lp(a) and FH phenotype were both significant determinants in predicting the early onset and severity of CAD. Subsequently, patients with Lp(a)-HLP in definite/probable FH increased significantly the CAD risk (all p < 0.05). CONCLUSIONS Lp(a) levels were higher in patients with FH phenotype than in those without, but no difference were found in FH patients of different mutated backgrounds. Moreover, Lp(a) and FH played a synergistic role in predicting the early onset and severity of CAD.