Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands.
Department of Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands.
Atherosclerosis. 2020 Aug;306:15-21. doi: 10.1016/j.atherosclerosis.2020.07.001. Epub 2020 Jul 6.
The rare ASGR1 del12 variant is associated with a beneficial effect on coronary artery disease (CAD) that is disproportionate to the small reductions in plasma LDL cholesterol (LDLc). This unexplained benefit has sparked the debate on potential additional pleiotropic effects of ASGR1 variants. Since ASGR1 has also been implicated in platelet homeostasis, we evaluated platelet function in heterozygous ASGR1 del12 carriers and controls. In addition, we compared the magnitude of various LDLc lowering genetic scores in the UK-biobank using Mendelian randomization.
Desialylation of platelet surface glycoproteins and platelet aggregation capacity were measured in 12 carriers and 10 controls. We selected 3 common genetic variants in the ASGR1 locus that were significantly associated with plasma LDLc and assessed the association with coronary artery disease (CAD) and compared it with the effects of HMCGR, LDLR, NCI1L1 and PCSK9 gene scores.
Platelet surface GlcNAC residues were significantly lower in carriers but platelet aggregation did not differ. The relative risk reduction of ASGR1 GRS on CAD and myocardial infarction per 10 mg/dl LDLc reduction was 23% (OR 0.77, 95% CI 0.62-0.96). This risk reduction was proportionally similar to the gene risk scores in HMCGR, NPC1L1, PCSK9, and LDLR.
Unlike previous reports, we did not find any evidence for a pleiotropic effect of the rare del12 variant in the ASGR1 locus on CAD, as platelet function did not differ between carriers and controls. Moreover, the observed effect of ASGR1 variants on CAD risk was proportional to the reduction in plasma LDLc levels.
罕见的 ASGR1 del12 变异与冠心病（CAD）的有益影响相关，这种影响与血浆 LDL 胆固醇（LDLc）的微小降低不成比例。这种无法解释的益处引发了关于 ASGR1 变异可能存在额外的多效性作用的争论。由于 ASGR1 也与血小板稳态有关，我们评估了杂合子 ASGR1 del12 携带者和对照组的血小板功能。此外，我们使用孟德尔随机化比较了 UK-biobank 中各种 LDLc 降低遗传评分的幅度。
测量了 12 名携带者和 10 名对照者血小板表面糖蛋白的去唾液酸化和血小板聚集能力。我们选择了 ASGR1 基因座上的 3 个常见遗传变异，这些变异与血浆 LDLc 显著相关，并评估了它们与 CAD 的相关性，并将其与 HMCGR、LDLR、NCI1L1 和 PCSK9 基因评分的影响进行了比较。
携带者的血小板表面 GlcNAC 残基明显降低，但血小板聚集没有差异。每降低 10mg/dl LDLc，ASGR1 GRS 对 CAD 和心肌梗死的相对风险降低 23%（OR 0.77，95%CI 0.62-0.96）。这种风险降低与 HMCGR、NPC1L1、PCSK9 和 LDLR 中的基因风险评分比例相似。
与之前的报告不同，我们没有发现 ASGR1 基因座上罕见的 del12 变异对 CAD 的多效性影响的任何证据，因为携带者和对照组的血小板功能没有差异。此外，ASGR1 变异对 CAD 风险的影响与血浆 LDLc 水平的降低成正比。
