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.

家族性高胆固醇血症 (FH) 是一种常染色体显性遗传的单基因疾病，其特征是低密度脂蛋白胆固醇 (LDL-C) 水平升高和早发性冠状动脉疾病 (CAD) 的风险增加。最近，研究表明，高多基因风险评分 (PRS) 可能是欧洲血统 FH 患者 CAD 的独立危险因素。然而，尚不确定 PRS 是否也可用于东亚 FH 患者的风险分层。我们从金泽大学孟德尔病 FH 登记处招募临床诊断的 FH (CDFH) 患者并进行基因分型，并从日本 Shikamachi 健康改善实践基因组队列中进行对照。我们从每个参与者的 360 万个变体（根据 1000 个基因组 3 期亚洲数据集估算）中计算了 LDL-C（PRS _LDLC) 使用来自 BioBank Japan Project 的全基因组关联研究汇总统计数据。我们评估了 PRS _LDLC与单基因 FH、突变阴性 CDFH 和对照之间和内部的 LDL-C 和 CAD 的关联。我们测试了总共 1223 名参与者（376 名 FH 患者，包括 173 名单基因 FH 和 203 名突变阴性 CDFH，以及 847 名对照）进行分析。突变阴性 CDFH 患者的PRS _LDLC显着高于对照组 ( p  = 3.1 × 10 ^-13 )。PRS _LDLC也与对照组的 LDL-C 显着相关（p趋势 = 3.6 × 10 ^-4），但在 FH 患者中没有。此外，我们无法检测到 PRS _{LDLC之间的任何关联}和任何组中的 CAD。总之，突变阴性 CDFH 患者的 PRS _LDLC显着高于对照组。然而，PRS _LDLC可能对 FH 患者的 LDL-C 和 CAD 几乎没有额外影响。