Background

Cardiovascular disease (CVD) is a major cause of mortality and morbidity. Increased low-density lipoprotein cholesterol (LDL-C) level is its major risk factor. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated LDL-C since birth and subsequent premature CVD. There is a heterogeneity in the CVD onset in patients with FH. This is potentially due to the presence of other independent risk factors. Lipoprotein(a) [Lp(a)] is an LDL-like particle and represents a strong risk factor for CVD.

Objective

Our objective was to understand the contribution of Lp(a) in the susceptibility to CVD in individuals with genetic diagnosis of FH.

Methods

We measured Lp(a) levels in 2 independent and well-characterized genetic-FH cohorts: the FH-Gothenburg cohort (n = 190) and the FH-CEGP Milan cohort (n = 160). The genetic diagnosis was performed by targeted next-generation sequencing (FH-Gothenburg and part of the FH-CEGP Milan cohort), or by Sanger sequencing.

Results

We show that among individuals with genetic diagnosis of FH, those with previous CVD had higher Lp(a) levels. In addition, analyzing the response to the lipid-lowering therapies, we have also shown that statins had the same LDL-C–lowering effect irrespective of the type of FH-causative mutation. However, when we examined the lipid-lowering effect of proprotein convertase subtilisin/kexin type 9 inhibition by antibodies, we observed a trend in a better reduction of the LDL-C level in carriers of nonsense mutations.

Conclusion

In conclusion, our results suggest that Lp(a) contributes to CVD onset in individuals with genetic diagnosis of FH. Our finding supports the importance to identify an efficacious therapy to lower Lp(a) in patients with FH to prevent CVD onset or recurrence.

中文翻译：

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患有家族性高胆固醇血症和心血管事件的个体的循环Lp（a）水平较高。

背景

心血管疾病（CVD）是死亡率和发病率的主要原因。低密度脂蛋白胆固醇（LDL-C）水平升高是其主要危险因素。家族性高胆固醇血症（FH）是一种遗传性疾病，其特征是自出生和随后的过早CVD以来，LDL-C升高。FH患者的CVD发作存在异质性。这可能是由于存在其他独立的风险因素所致。脂蛋白（a）[Lp（a）]是一种LDL样颗粒，是CVD的重要危险因素。

客观的

我们的目标是了解患有LH（a）的FH遗传诊断患者对CVD易感性的贡献。

方法

我们在2个独立且特征明确的遗传FH队列中测量了Lp（a）水平：FH-Gothenburg队列（n = 190）和FH-CEGP Milan队列（n = 160）。遗传诊断通过靶向的下一代测序（FH-Gothenburg和FH-CEGP Milan队列的一部分）或通过Sanger测序进行。

结果

我们显示，在具有FH遗传学诊断的个体中，先前患有CVD的个体具有更高的Lp（a）水平。此外，分析对降脂疗法的反应，我们还发现他汀类药物具有相同的降低LDL-C的作用，而与FH致突变的类型无关。但是，当我们检查抗体对前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型的脂质降低作用时，我们观察到了无意义突变携带者中LDL-C水平更好降低的趋势。

结论

总之，我们的结果表明，Lp（a）有助于患有FH遗传学诊断的个体的CVD发作。我们的发现支持了确定有效的治疗以降低FH患者的Lp（a）以预防CVD发作或复发的重要性。