Epidemiology and Preventive Pharmacology Service (SEFAP) Department of Pharmacological and Biomolecular Sciences University of Milan Italy.
Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy.
J Am Heart Assoc. 2022 Apr 5;11(7):e023668. doi: 10.1161/JAHA.121.023668. Epub 2022 Mar 24.
Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, <0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, <0.0001; 250-349 mg/dL: 1.02 versus 0.95, =0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice.
临床上诊断为家族性高胆固醇血症（FH）但没有任何致病突变的患者，很可能患有多基因高胆固醇血症。我们评估了包含 12 个低密度脂蛋白胆固醇（LDL-C）升高变异的多基因风险评分（多基因 LDL-C 风险评分）在 FH 临床诊断患者中的分布情况。
在脂质转运障碍意大利遗传网络（LIPIGEN）研究中，对 875 名 FH 基因突变阳性的患者（女性占 54.75%；平均年龄 42.47±15.00 岁）和 644 名 FH 基因突变阴性的患者（女性占 54.21%；平均年龄 49.73±13.54 岁）进行了评估。FH 基因突变阴性的患者治疗前 LDL-C 水平低于 FH 基因突变阳性的患者（217.14±55.49 比 270.52±68.59 mg/dL，<0.0001）。FH 基因突变阴性的患者的多基因 LDL-C 风险评分平均值（±SD）为 1.00（±0.18），而 FH 基因突变阳性的患者为 0.94（±0.20）（<0.0001）。在受试者工作特征分析中，多基因高胆固醇血症患者的曲线下面积为 0.59（95%CI，0.56-0.62），敏感性和特异性分别为 78%和 36%，截断值为 0.905。在 LDL-C 水平在 150 至 350mg/dL 范围内的 FH 基因突变阴性患者中，观察到更高的多基因 LDL-C 风险评分水平（150-249mg/dL：1.01 比 0.91，<0.0001；250-349mg/dL：1.02 比 0.95，=0.0001）。FH 患者中，无论是否存在致病突变，多基因 LDL-C 风险评分与治疗前 LDL-C 水平之间均存在正相关。
该分析证实了多态性在调节 LDL-C 水平方面的作用，即使在基因确诊的 FH 患者中也是如此。需要更多的数据来支持在常规临床实践中使用多基因评分。
