ASGR1 基因座中的常见基因变异与不存在多效作用的心血管风险降低有关,Atherosclerosis

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ASGR1 基因座中的常见基因变异与不存在多效作用的心血管风险降低有关
Atherosclerosis ( IF 4.9 ) Pub Date : 2020-08-01 , DOI: 10.1016/j.atherosclerosis.2020.07.001
Lubna Ali ₁ , Arjen J Cupido ₂ , Maaike Rijkers ₃ , G Kees Hovingh ₂ , Adriaan G Holleboom ₂ , Geesje M Dallinga-Thie ₄ , Erik S G Stroes ₂ , Marjolein A W van den Boogert ₂

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背景和目的罕见的 ASGR1 del12 变异与对冠状动脉疾病 (CAD) 的有益影响有关，这与血浆 LDL 胆固醇 (LDLc) 的小幅降低不成比例。这种无法解释的好处引发了关于 ASGR1 变体潜在的额外多效性影响的争论。由于 ASGR1 也与血小板稳态有关，我们评估了杂合 ASGR1 del12 携带者和对照的血小板功能。此外，我们使用孟德尔随机化比较了英国生物库中各种 LDLc 降低遗传评分的幅度。方法在12个载体和10个对照中测量血小板表面糖蛋白的去唾液酸化和血小板聚集能力。我们在 ASGR1 基因座中选择了 3 个与血浆 LDLc 显着相关的常见遗传变异，并评估了与冠状动脉疾病 (CAD) 的关联，并将其与 HMCGR、LDLR、NCI1L1 和 PCSK9 基因评分的影响进行了比较。结果携带者的血小板表面 GlcNAC 残留显着降低，但血小板聚集没有差异。每 10 mg/dl LDLc 降低 ASGR1 GRS 对 CAD 和心肌梗塞的相对风险降低为 23%（OR 0.77，95% CI 0.62-0.96）。这种风险降低与 HMCGR、NPC1L1、PCSK9 和 LDLR 中的基因风险评分成比例地相似。结论与之前的报告不同，我们没有发现任何证据表明 ASGR1 基因座中罕见的 del12 变异对 CAD 具有多效性，因为携带者和对照之间的血小板功能没有差异。而且，

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Common gene variants in ASGR1 gene locus associate with reduced cardiovascular risk in absence of pleiotropic effects

BACKGROUND AND AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

更新日期：2020-08-01

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