Center for Genomic Medicine, Massachusetts General Hospital, Richard B. Simches Research Center, 185 Cambridge Street, CPZN 6818, Boston, MA, 02114, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Boston, MA, USA.
BMC Med. 2022 Aug 11;20(1):245. doi: 10.1186/s12916-022-02446-6.
Interleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors.
Among 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors.
The study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06-1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL.
Any benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.
白细胞介素 6（IL-6）信号转导被认为是治疗动脉粥样硬化性心血管疾病（CVD）的靶点。虽然循环中高敏 C 反应蛋白（hsCRP）的变化被用作 IL-6 信号转导的标志物，但尚不清楚其是否与基线 hsCRP 水平或其他心血管危险因素有关。本研究旨在探讨与基线 hsCRP 水平和心血管危险因素分层人群中遗传预测的 IL-6 信号与 CVD 风险的相关性。
在 397060 名没有基线 CVD 的白种英国 UK Biobank 参与者中，我们计算了由 IL6R 基因座上的 26 个变体组成的 IL-6 受体（IL-6R）介导信号的遗传风险评分。然后，我们应用线性和非线性孟德尔随机化分析来探索与复合终点（包括冠状动脉疾病、缺血性中风、外周动脉疾病、主动脉瘤和心血管死亡）的关联，该终点根据基线 hsCRP 水平和心血管危险因素进行分层。
研究参与者（中位年龄 59 岁，53.9%为女性）的中位随访时间为 8.8 年，在此期间共发生 46033 例心血管事件。遗传预测的 IL-6R 介导的信号活性与更高的 CVD 风险相关（每增加 1mg/dL 绝对 hsCRP 水平的 HR：1.11，95%CI：1.06-1.17）。CVD 风险的增加与基线绝对 hsCRP 水平呈线性相关。在按性别、年龄、体重指数、估计肾小球滤过率或收缩压对人群进行分层时，遗传预测的 IL-6R 介导的信号与 CVD 风险的关联没有异质性，但在低密度脂蛋白胆固醇≥160mg/dL 的个体中，关联更强。
抑制 IL-6 信号转导以降低 CVD 风险的任何益处可能与 hsCRP 水平的绝对降低成正比。因此，为了降低 CVD 风险，治疗性抑制 IL-6 信号转导应优先考虑基线 hsCRP 水平最高的个体。
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