Department of Neurology and Stroke Center, University Hospital Basel, Switzerland; Department of Clinical Research, University of Basel, Switzerland.
Department of Neurology and Stroke Center, University Hospital Basel, Switzerland; Department of Clinical Research, University of Basel, Switzerland.
Atherosclerosis. 2022 Nov;361:41-46. doi: 10.1016/j.atherosclerosis.2022.09.007. Epub 2022 Sep 26.
Post hoc analyses of clinical trials show that PCSK9 inhibitors might lower lipoprotein(a), but whether this effect contributes to reductions in cardiovascular risk remains unknown. We aimed to assess whether genetically proxied PCSK9 inhibition influences lipoprotein(a) (Lp(a)), and whether any such effect could mediate its effects on coronary artery disease (CAD) and ischemic stroke (IS).
To explore associations between the genetic proxies for PCSK9 inhibitors and Lp(a) levels, we used UK Biobank data (310,020 individuals). We identified 10 variants in the PCSK9 gene associated with lower PCSK9 and LDL-C levels as proxies for PCSK9 inhibition. We explored the effects of genetically proxied PCSK9 inhibition on Lp(a) levels, as well as on odds of CAD (60,801 cases, 184,305 controls) and IS (60,341 cases, 454,450 controls) in two-sample Mendelian randomization analyses. In mediation analyses, we assessed the effects of genetically proxied PCSK9 inhibition on CAD and IS mediated through reductions in Lp(a) levels.
Genetically proxied PCSK9 inhibition (1-SD decrement in PCSK9 concentration; corresponding to 20.6 mg/dl decrement in LDL-C levels) was associated with a 4% decrease in log-Lp(a) levels (beta: -0.038, 95%CI: -0.053 to -0.023). We estimated a 0.8% reduction in the odds for CAD (OR: 0.992, 95%CI: 0.989-0.995) and a 0.5% reduction in the odds for atherosclerotic IS (OR: 0.995, 95%CI: 0.992-0.998) due to reductions in Lp(a) levels through genetically proxied PCSK9 inhibition, corresponding to 3.8% and 3.2% of the total effects, respectively.
Genetic proxies for PCSK9 inhibition are associated with lower Lp(a) levels. However, Lp(a) lowering explains only a small proportion of the total effects of genetic proxies for PCSK9 inhibitors on risk of CAD and IS.
临床试验的事后分析表明，PCSK9 抑制剂可能会降低脂蛋白(a)，但这种作用是否有助于降低心血管风险尚不清楚。我们旨在评估遗传上与 PCSK9 抑制剂相关的脂蛋白(a)（Lp(a)）是否会受到影响，以及这种影响是否可以介导其对冠状动脉疾病（CAD）和缺血性中风（IS）的影响。
为了探讨 PCSK9 抑制剂的遗传替代物与 Lp(a)水平之间的关联，我们使用了英国生物库数据（310,020 人）。我们确定了 PCSK9 基因中的 10 个变体，这些变体与较低的 PCSK9 和 LDL-C 水平相关，可作为 PCSK9 抑制的替代物。我们通过两样本 Mendelian 随机分析探讨了遗传上与 PCSK9 抑制剂相关的 PCSK9 抑制对 Lp(a)水平的影响，以及对 CAD（60,801 例病例，184,305 例对照）和 IS（60,341 例病例，454,450 例对照）的影响。在中介分析中，我们评估了遗传上与 PCSK9 抑制剂相关的 PCSK9 抑制通过降低 Lp(a)水平对 CAD 和 IS 的影响。
遗传上与 PCSK9 抑制剂相关的 PCSK9 抑制（PCSK9 浓度 1-SD 降低；相当于 LDL-C 水平降低 20.6mg/dl）与 Lp(a)水平降低 4%相关（β：-0.038，95%CI：-0.053 至-0.023）。我们估计 Lp(a)水平降低导致 CAD 的几率降低 0.8%（OR：0.992，95%CI：0.989-0.995），动脉粥样硬化性 IS 的几率降低 0.5%（OR：0.995，95%CI：0.992-0.998），这相当于通过遗传上与 PCSK9 抑制剂相关的 PCSK9 抑制对 CAD 和 IS 的总效应的 3.8%和 3.2%。
PCSK9 抑制剂的遗传替代物与较低的 Lp(a)水平相关。然而，Lp(a)降低仅解释了遗传上与 PCSK9 抑制剂相关的 PCSK9 抑制剂对 CAD 和 IS 风险的总效应的一小部分。
