National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australia (E.P.).
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (E.P., M.S., J.E.P., B.B.S., A.S.B., J.D., D.F.F., D.S.P.), University of Cambridge, United Kingdom.
Circ Genom Precis Med. 2019 Feb;12(2):e002413. doi: 10.1161/CIRCGEN.118.002413.
The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection.
Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death.
After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P<0.05).
Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.
白细胞介素（IL）-6 受体（IL6R）基因中的 Asp358Ala 变异（rs2228145；A>C）与腹主动脉瘤（AAA）的发生有关，但该变异对 AAA 随时间增长的影响尚不清楚。我们旨在研究 IL6R-Asp358Ala 变异与 AAA 增长的临床关联，并评估在腹主动脉瘤破裂或夹层的小鼠模型中阻断 IL-6 信号通路的效果。
利用来自 9 个前瞻性队列的 2863 名 AAA 患者的数据，使用年龄和性别调整的混合效应线性回归模型来估计 IL6R-Asp358Ala 变异与 AAA 直径每年变化（mm/y）之间的关系。在一系列补充的、针对小鼠的随机试验中，评估了阻断 IL-6 信号通路对血浆生物标志物、收缩压、动脉瘤直径以及主动脉破裂和死亡时间的影响。
在调整年龄和性别后，次要等位基因 [C] 每增加一个拷贝，基线动脉瘤大小就会小 0.55mm（95%CI，0.13-0.98mm）。AAA 生长的变化为每年减少 0.06mm（-0.18 至 0.06），这一结果无统计学意义。尽管使用了所有可获得的全球数据，但遗传分析的效力不足以检测到如此小的效应大小。在 2 个 AAA 小鼠模型中，选择性阻断 IL-6 转导信号通路，但不是同时阻断经典和转导信号通路，与生存率的提高相关（P<0.05）。
我们的初步研究数据与 IL-6 转导信号与 AAA 生长相关的概念一致，这鼓励对这一假设进行更大规模的评估。
