Association of LDL-C/ApoB ratio with pathogenic variants in familial hypercholesterolemia

Introduction Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism marked by elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Conventional diagnostic tools such as the Dutch Lipid Clinic Network (DLCN) score do not assess qualitative differences in lipoprotein composition. The LDL-C/Apolipoprotein B (ApoB) ratio approximates cholesterol content per atherogenic particle. We hypothesized that the LDL-C/ApoB ratio differs by genetic FH status and its response to modern lipid-lowering regimens and may provide incremental diagnostic discrimination beyond the DLCN score. Methods We analysed all patients of a tertiary lipid clinic with untreated LDL-C ≥160 mg/dL and/or DLCN Score ≥4 with available LDL-C and ApoB measurements that underwent genetic testing for FH (n=113). Genetic FH status was defined according to ACMG classification: pathogenic or likely pathogenic variants (ACMG class ≥4) were classified as FH-positive (mut+) whereas patients without these variants were classified as FH-negative (mut-). The LDL-C/ApoB ratio was assessed at baseline and under selected lipid-lowering regimens (e.g.: high-dose statin + ezetimibe; high-dose statin + ezetimibe + PCSK9 inhibitor). Group comparisons used non-parametric testing. Diagnostic performance for genetically confirmed FH was evaluated using ROC analysis comparing the DLCN score alone versus DLCN plus LDL-C/ApoB ratio, with DeLong testing for differences in AUC. Results At baseline, genetically confirmed FH (mut+) exhibited a significantly higher LDL-C/ApoB ratio than FH-negative (mut−) patients (median 1.32 vs 1.26; p = 0.035), consistent with a more cholesterol-enriched LDL particle phenotype in monogenic FH. Intensive lipid-lowering therapy reduced the ratio overall, but between-group differences persisted under high-dose statin plus ezetimibe (median 1.06 vs 0.84; p < 0.001) and after additional PCSK9 inhibition (median 0.77 vs 0.50; p < 0.001). For discrimination of genetically confirmed FH, the DLCN score alone showed moderate accuracy (AUC 0.713, 95% CI 0.567–0.859), and adding the untreated LDL-C/ApoB ratio did not improve discrimination (AUC 0.719, 95% CI 0.571–0.866; ΔAUC DeLong p = 0.623). Conclusion In this hypercholesterolemic cohort, the LDL-C/ApoB ratio identifies biologically meaningful differences in lipoprotein composition between genetically defined FH and non-FH individuals and reflects treatment-induced lipoprotein remodelling. However, it provides limited incremental diagnostic value beyond the DLCN score. The LDL-C/ApoB ratio may therefore serve as a complementary biomarker of lipoprotein quality and therapeutic response rather than a primary diagnostic tool for FH.