Mutation Spectrum And Polygenic Score In German Patients With Familial Hypercholesterolemia

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: theLDL receptorgene (LDLR), theapolipoprotein Bgene (APOB) and theproprotein convertase subtilisin/kexin 9gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations inLDLR,APOB, andPCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in theLDLRgene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P< .05) and healthy controls (P< .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.