Background and aims

Lipoprotein(a) [Lp(a)] concentration in heterozygous familial; hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown.

We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH.

Methods

We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers’ Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort.

Results

Adjusted geometric means (95% confidence interval) of Lp(a) in controls ^{(n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL} (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4).

These differences were also observed in heFH from the SEA cohort. The number of ^{plasminogen-like kringle IV type−2 repeats of LPA, the hypercholesterolemia polygenic} score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain.

Conclusions

Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc.

中文翻译：

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遗传性高胆固醇血症中的脂蛋白（a）。遗传原因、缺陷基因和突变类型的影响

背景和目标

杂合子家族中的脂蛋白(a) [Lp(a)] 浓度；高胆固醇血症（heFH）尚未完全确定。导致 heFH 的遗传缺陷是否在 Lp(a) 浓度中起作用尚不清楚。

我们旨在比较健康人群、基因诊断的 heFH 和突变阴性高胆固醇血症受试者中的 Lp(a)，并评估导致 heFH 的遗传缺陷对 Lp(a) 的影响。

方法

我们在西班牙的一家脂质诊所进行了一项横断面研究。我们研究了疑似 heFH 的成年人，并对 FH 基因（LDLR、APOB、APOE和PCSK9）的遗传研究以及来自 de Aragon 工人健康研究的对照进行了研究。来自西班牙动脉粥样硬化协会 (SEA) 血脂异常登记处的 HeFH 患者被用作验证队列。

结果

^{对照组(n = 1059)、heFH (n = 500) 和突变阴性受试者 (n = 860)}中 Lp(a) 的调整几何平均值 (95% 置信区间)为 14.9 mg/dL (13.6, 16.4),在所有比较中，21.9 mg/dL (18.1, 25.6) 和 37.4 mg/dL (33.3, 42.1)，p  < 0.001。在 heFH 受试者中，依赖APOB的 FH 表现出最高的 Lp(a)，为 36.5 mg/dL (22.0, 60.8)，其次是依赖LDLR的FH，为 21.7 mg/dL (17.9, 26.4)。

在来自 SEA 队列的 heFH 中也观察到了这些差异。^LPA的^{纤溶酶原样 kringle IV type-2 重复数、高胆固醇血症多基因}评分或 LDLc 浓度不能解释这些差异。在依赖于LDLR的 FH 中，Lp(a) 水平不因受影响的蛋白质结构域而异。

结论

Lp(a) 在突变阴性受试者和 heFH 中升高。heFH 中 Lp(a) 的浓度随相关基因而变化。heFH 中较高的 Lp(a) 不能用较高的 LDLc 来解释。