目的:家族性高胆固醇血症(FH)是一种遗传性疾病,其特征是高LDL胆固醇和过早冠状动脉疾病(CAD)风险增加。当前LDL受体基因(LDLR)变体的二分法分类可能不足以捕获患者LDL胆固醇水平和CAD风险的变异性。这项研究评估了使用变体特异性LDL胆固醇百分位数确定LDLR变体严重程度的新方法。
方法:对荷兰FH级联筛选计划的参与者进行了456种LDLR变体的筛选。对于每个LDLR变体载波,性别和年龄特异性LDL胆固醇百分位数来自研究进入时测量的LDL胆固醇水平,即通常从用于DNA分析的血液中抽取。这些百分位数用于计算每个变体的平均LDL胆固醇百分位数。基于变异特异性LDL胆固醇百分位数,携带者分为以下LDL胆固醇层:<75岁,75-88岁,第88-92,第92-96.5,96.5-98,且≥第98百分位数。此外,变异分为1类(LDLR缺陷型)和非1类(通常为LDLR缺陷型)变异型.使用Cox比例风险模型比较了不同LDL胆固醇层中的携带者与非携带者之间的CAD风险。
结果:在35,067名参与者中,12,485(36%)LDLR变异携带者(平均年龄38.0±20.0岁,47.7%的男性)被鉴定。与非携带者相比,携带者的CAD风险高5倍。在整个LDL胆固醇层中,CAD的危险比从2.2(95CI0.97-5.0)逐渐增加到12.0(95CI5.5-24.8)。在1类和非1类LDLR变体的携带者中观察到CAD风险增加7.3倍和3.9倍。分别。
结论:本研究提出了一种基于LDLR变体对LDL胆固醇水平的影响进行分类的精细方法。允许更精确的,与传统方法相比,在FH患者中基因型特异性CAD风险估计。
OBJECTIVE: Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles.
METHODS: Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model.
RESULTS: Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively.
CONCLUSIONS: This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods.