Background and Aims

Background: A polygenic background can be recognized in part of patients with clinically diagnosed familial hypercholesterolemia (FH). The phenotypical distinction between monogenic (due to causative mutations in major LDLR, APOB or PCSK9 genes) and polygenic FH is not completely clarified.

Aims: We aimed to compare the clinical phenotype and response to treatment in monogenic vs. polygenic FH

Methods

Methods: Five hundred patients with clinical FH diagnosed based upon DLCNC> 3 were genotyped. Causative monogenic variants were identified by NGS and the polygenic score (GRS) was estimated by the 6-LDL-rising SNPs panel. Patients’ clinical characteristic and LDL-C changes during cholesterol-lowering treatments were retrospectively obtained.

Results

Results: 323 (64.6%) patients were FH-mutation positive (monogenic FH) and 177 (35.4%) patients were classified as FH-mutation negative (FH/M-). In comparison with normocholesterolemic subjects, FH/M- patients had higher mean GRS (0.71± 0.19 and 0.61±0.20, p<0.001). Based on a GRS value above 0.69 (the best cut-off discriminating FH/M– and normocholesterolemic individuals), 21% of clinically diagnosed FH were classified as polygenic. Polygenic FH were older and showed lower untreated total and LDL-C as compared to monogenic FH. During about 33 months of follow-up, monogenic FH showed higher on-treatment, last visit and best LDL-C as compared with FH/M- patients (P<0.005). These differences persisted even after adjustment for intensity of cholesterol-lowering therapies.

Conclusions

Conclusions: Our results highlight that a polygenic GRS might explain the elevation of LDL-C observed in FH/M- patients. In these patients, the burden of LDL-C is lower than that in monogenic FH patients.