The impact of gene variants on the thickness and softness of the Achilles tendon in familial hypercholesterolemia

Background and aims: Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL)-cholesterol, xanthoma of the Achilles tendon (AT), and premature coronary artery disease (CAD). Ultrasonography can assess AT thickness and softness, making it useful for evaluating AT in FH diagnosis. We aimed to clarify whether FH-causative LDLR or PCSK9 variants affect AT thickness or softness. Methods: In total, 248 FH and 60 non-familial hypercholesterolemia (non-FH) patients (total: 308) aged >= 30 years were enrolled. Patients with FH were classified according to genotype. AT thickness and elasticity index (EI) as softness were measured by ultrasonography. Results: In FH patients with LDLR variants, AT was significantly thicker and softer than it was in FH patients with PCSK9 variants, FH patients without LDLR or PCSK9 variants, and patients with non-FH. The proportion of patients harboring LDLR variants significantly increased with AT thickness (p = 2.0 x 10(-31)) and softness (p = 1.4 x 10(-18)). Among those with AT thickness>8.5 mm and EI < 3.9, patients with LDLR variants accounted for 89% and 83%, respectively. The odds of AT thickening, AT softening and CAD increased 13.3-fold, 4.9-fold, and 2.1-fold, adjusted for the LDL-C year score by the presence of LDLR variants compared with those of patients without LDLR or PCSK9 variants. PCSK9 variants did not influence AT thickening or softening or CAD prevalence. Conclusions: LDLR variants affected AT thickness and softness independent of the LDL-C year score, but PCSK9 variants did not. Evaluating AT is important for identifying FH patients with LDLR variants at high risk for CAD.

Automated summary

This study found a significant correlation between LDLR gene variants and AT thickness and softness, while PCSK9 gene variants were not associated. Evaluating AT is important for identifying FH patients with LDLR gene variants at high risk for CAD.