Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRS_LDLC) using a genome-wide association study summary statistic from the BioBank Japan Project. We assessed the association of PRS_LDLC with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRS_LDLC was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10⁻¹³). PRS_LDLC was also significantly linked to LDL-C in controls (p trend = 3.6 × 10⁻⁴) but not in FH patients. Moreover, we could not detect any association between PRS_LDLC and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRS_LDLC than controls. However, PRS_LDLC may have little additional effect on LDL-C and CAD among FH patients.