Tada Hayato, Kojima Nobuko, Yamagami Kan, Nomura Akihiro, Nohara Atsushi, Usui Soichiro, Sakata Kenji, Hayashi Kenshi, Fujino Noboru, Takamura Masayuki, Kawashiri Masa-Aki
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
J Clin Lipidol. 2022 Nov-Dec;16(6):863-869. doi: 10.1016/j.jacl.2022.09.007. Epub 2022 Sep 30.
Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited.
To investigate the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and occurrence of major adverse cardiac events (MACEs), in FH patients (N = 1050, male/female = 490/560).
We retrospectively assessed the data of patients with FH admitted at Kanazawa University Hospital between 1990 and 2020. Based on genotype, the patients were divided into patients without variants, with VUS of LDLR, and with pathogenic variants. Cox proportional hazard model was used to identify the factors associated with MACEs.
The median follow-up duration was 12.6 years (interquartile range: 9.5-17.9 years). Altogether, 777 patients had FH mutation and 273 had pathogenic mutation, with 92 having VUS. Over the follow-up duration, 175 MACEs were observed. LDL cholesterol level was found to be significantly higher in patients with pathogenic variants (251 mg/dL) than in patients with VUS (225 mg/dL) and without variants (203 mg/dL). Pathogenic variants and VUS are significantly associated with MACEs (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.02-2.02, P = 0.033 and HR = 3.18, 95% CI = 2.00-4.36, P = 1.9 × 10, relative to patients without any variants, respectively), independent of classical risk factors.
VUS of LDLR was significantly associated with poor outcomes in FH patients. Genetic testing is useful for the diagnosis and risk stratification of FH patients.
关于低密度脂蛋白受体（LDLR）意义未明变异（VUS）对家族性高胆固醇血症（FH）表型影响的数据有限。
研究FH患者（N = 1050，男/女 = 490/560）的基因型与表型之间的关联，包括低密度脂蛋白（LDL）胆固醇水平和主要不良心脏事件（MACE）的发生情况。
我们回顾性评估了1990年至2020年间在金泽大学医院收治的FH患者的数据。根据基因型，将患者分为无变异、有LDLR的VUS和有致病变异的患者。采用Cox比例风险模型确定与MACE相关的因素。
中位随访时间为12.6年（四分位间距：9.5 - 17.9年）。共有777例患者有FH突变，273例有致病突变，92例有VUS。在随访期间，观察到175例MACE。发现有致病变异的患者LDL胆固醇水平（251 mg/dL）显著高于有VUS的患者（225 mg/dL）和无变异的患者（203 mg/dL）。致病变异和VUS与MACE显著相关（风险比[HR] = 1.52，95%置信区间[CI] = 1.02 - 2.02，P = 0.033；HR = 3.18，95% CI = 2.00 - 4.36，P = 1.9×10，相对于无任何变异的患者），独立于经典危险因素。
LDLR的VUS与FH患者的不良预后显著相关。基因检测对FH患者的诊断和风险分层有用。
