基因代理的IL-6信号抑制、脂蛋白（a）水平和动脉粥样硬化疾病风险
Genetically proxied IL-6 signaling inhibition, lipoprotein(a) levels, and atherosclerotic disease risk.
摘要(中文译文)
临床试验表明，白细胞介素-6（IL-6）信号通路抑制剂可降低脂蛋白(a)[Lp(a)]水平，但这一降低与动脉粥样硬化性心血管疾病（ASCVD）风险的相关性尚不明确。我们利用孟德尔随机化（MR）方法研究Lp(a)降低在多大程度上介导了IL-6信号抑制对ASCVD的影响。IL-6信号抑制由IL6R变异p.Asp358Ala作为代理指标，并按C反应蛋白（CRP）水平进行标度。Lp(a)的遗传关联数据来自英国生物银行（n = 343,681）。结局包括大动脉粥样硬化性卒中（LAAS：6,399例）、颈动脉斑块（29,760例）和冠状动脉疾病（CAD：181,522例）。MR分析估计了IL-6信号抑制与Lp(a)及ASCVD的关联，并量化了Lp(a)介导的IL-6-ASCVD关联的比例。个体水平分析检验了在Lp(a)升高变异的携带者中，IL-6信号抑制对Lp(a)和CAD的效应是否被放大。遗传代理的IL-6信号抑制适度降低了Lp(a)（每降低1-ln(CRP)为-3.01 mg/dL，95% CI -4.79，-1.23），并对所有ASCVD结局均具有保护作用（OR：0.34-0.69）。Lp(a)仅介导了IL-6-ASCVD关联的一小部分（范围：1.3%-4.8%）。在Lp(a)升高变异的携带者中，IL-6-Lp(a)关联更强（-9.8 mg/dL，95% CI -14.6，-5.1；p = 6.38 × 10），但IL-6-CAD关联相似（p = 0.75），且中介比例仍然较低（4.2%-15.6%）。这些发现表明，Lp(a)对IL-6信号抑制的心血管获益介导作用极小，且不产生修饰效应，支持这些靶点作为ASCVD的独立且互补的治疗靶点。在Lp(a)升高变异携带者中IL-6-Lp(a)关联的放大效应值得进一步验证。
Abstract
Clinical trials have shown that interleukin-6 (IL-6) signaling inhibitors reduce lipoprotein(a) [Lp(a)] levels, though the relevance of this reduction to atherosclerotic cardiovascular disease (ASCVD) risk is uncertain. We leveraged Mendelian randomization (MR) to investigate the extent to which Lp(a) reduction mediates the effects of IL-6 signaling inhibition on ASCVD. IL-6 signaling inhibition was proxied by the IL6R variant p.Asp358Ala and scaled to C-reactive protein (CRP) levels. Genetic associations with Lp(a) were obtained from UK Biobank (n = 343,681). Outcomes included large-artery atherosclerotic stroke (LAAS: 6399 cases), carotid plaque (29,760 cases), and coronary artery disease (CAD: 181,522 cases). MR analyses estimated the association of IL-6 signaling inhibition with Lp(a) and ASCVD, and we quantified the proportion of the IL-6-ASCVD association mediated by Lp(a). Individual-level analyses tested whether effects of IL-6 signaling inhibition on Lp(a) and CAD were amplified in carriers of Lp(a)-raising variants. Genetically proxied IL-6 signaling inhibition modestly reduced Lp(a) (-3.01 mg/dL per 1-ln(CRP) reduction, 95% CI -4.79, -1.23) and protected against all ASCVD outcomes (ORs: 0.34-0.69). Lp(a) mediated only a small proportion of the IL-6-ASCVD association (range: 1.3%-4.8%). In carriers of Lp(a)-raising variants, the IL-6-Lp(a) association was stronger (-9.8 mg/dL, 95% CI -14.6, -5.1; p = 6.38 × 10), though IL-6-CAD associations were similar (p = 0.75) and the proportion mediation remained low (4.2%-15.6%). These findings suggest that Lp(a) minimally mediates and does not modify the cardiovascular benefits of IL-6 signaling inhibition, supporting these targets as independent and complementary for ASCVD. The amplified IL-6-Lp(a) association in carriers of Lp(a)-raising variants warrants replication.
如何引用
AMA
Iyas Daghlas, Marios K Georgakis, Stephen O Brennan, Benoit J Arsenault, Stephen Burgess, Dipender Gill. Genetically proxied IL-6 signaling inhibition, lipoprotein(a) levels, and atherosclerotic disease risk.. Atherosclerosis. 2026; doi:10.1016/j.atherosclerosis.2026.120723.
APA
Iyas Daghlas, Marios K Georgakis, Stephen O Brennan, Benoit J Arsenault, Stephen Burgess, Dipender Gill (2026). Genetically proxied IL-6 signaling inhibition, lipoprotein(a) levels, and atherosclerotic disease risk.. Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2026.120723
GB/T 7714
Iyas Daghlas, Marios K Georgakis, Stephen O Brennan, Benoit J Arsenault, Stephen Burgess, Dipender Gill. Genetically proxied IL-6 signaling inhibition, lipoprotein(a) levels, and atherosclerotic disease risk.[J]. Atherosclerosis, 2026 doi:10.1016/j.atherosclerosis.2026.120723.
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