Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Smooth Muscle Cell Phenotypic Switch Induced by Traditional Cigarette Smoke Condensate: A Holistic Overview

“…Since the IL-6/STAT3 pathway can modulate SMC proliferation, migration, and expression of MMPs [ 47 ], reduced abundance of STATIP1 is a biochemical observation that properly fits with the behavior changes induced by exposing HSMC to CSC, as we described above. IL-6 is associated with an increased cardiovascular risk [ 48 ], and induces senescence-associated calcification of SMCs by activating the STAT3/p53/p21 signalling pathway [ 49 ]. Therefore, the CSC stimulation in SMCs may even be related to in vivo atherosclerotic lesion calcification by inducing IL-6 upregulation and reducing STATIP1 occurrence.…”

Proteogenomic integration reveals CXCL10 as a potentially downstream causal mediator for IL-6 signaling on atherosclerosis

“…To construct an instrument for IL-6R-mediated signaling, 19 we used variants within the IL6R gene or a region 300 kB upstream or downstream of it. In accordance with an approach that we previously described, 17, 18 we selected variants associated in a GWAS meta-analysis of 522,681 individuals with circulating levels of C-reactive protein (CRP), a downstream biomarker of IL-6 signaling 7 that was used as a functional readout for IL-6 signaling activity. The methodology and criteria used to obtain this instrument are outlined in the Supplementary Methods and the comprising genetic variants are listed in Supplementary Table S1 .…”

“…We previously leveraged genetic data from large-scale population-based studies and detected 26 variants in the gene encoding IL-6R that mimic the effects of pharmacologically inhibiting this protein. 17, 18 Here, we expand these analyses to blood proteomic data derived from the INTERVAL study (n=3,301) in order to explore: (i) the causal circulating signature of interfering with IL-6 signaling that could inform the discovery of biomarker signatures of drug response to IL-6 inhibitors, and (ii) potential mediators of the favorable cardiovascular effects of IL-6 inhibition that could serve as alternative and perhaps more selective drug targets. Following-up on our findings, we compare our results to those of clinical trials applying pharmacological inhibition of IL-6 signaling.…”

Mendelian randomization as a tool to inform drug development using human genetics

“…MR analyses may be designed to mimic these conditions and to test for heterogeneous effects across subgroups. This application is demonstrated by an MR analysis of genetically proxied inhibition of IL-6 signaling that stratified across numerous covariates including sex, age, kidney function, body mass index, LDL-cholesterol, blood pressure, and hemoglobin https://doi.org/10.1017/pcm.2023.5 Published online by Cambridge University Press Accepted Manuscript A1C (Georgakis, Malik, Richardson, et al, 2022). The relative benefit of inhibition of IL-6 signaling was consistent across strata of all covariates except for LDL-cholesterol, where a greater magnitude of benefit was seen at levels of LDL-cholesterol greater than 160mg/dL (Georgakis, Malik, Richardson, et al, 2022).…”

“…This application is demonstrated by an MR analysis of genetically proxied inhibition of IL-6 signaling that stratified across numerous covariates including sex, age, kidney function, body mass index, LDL-cholesterol, blood pressure, and hemoglobin https://doi.org/10.1017/pcm.2023.5 Published online by Cambridge University Press Accepted Manuscript A1C (Georgakis, Malik, Richardson, et al, 2022). The relative benefit of inhibition of IL-6 signaling was consistent across strata of all covariates except for LDL-cholesterol, where a greater magnitude of benefit was seen at levels of LDL-cholesterol greater than 160mg/dL (Georgakis, Malik, Richardson, et al, 2022). A larger absolute benefit was observed in the population subgroup with highest baseline high-sensitivity CRP levels, suggesting that clinical trials should prioritize this population for IL-6 inhibition therapies.…”