TY - JOUR
T1 - Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups
AU - Georgakis, Marios K.
AU - Malik, Rainer
AU - Richardson, Tom G.
AU - Howson, Joanna M. M.
AU - Anderson, Christopher D.
AU - Burgess, Stephen
AU - Hovingh, G. Kees
AU - Dichgans, Martin
AU - Gill, Dipender
N1 - Funding Information: MKG is supported by a Walter-Benjamin fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG], GZ: GE 3461/1-1) and the FöFoLe program of Ludwig-Maximilians-University Munich (FöFoLe-Forschungsprojekt Reg.-Nr. 1120). This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198 to MKG). CDA is supported by the US National Institutes of Health (R01NS103924, U01NS069763) and the American Stroke Association-Bugher Foundation. SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z) and supported by the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). MD received funding from the German Research Foundation (DFG) as part of the Collaborative Research Centre 1123 (B3). DG is supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London and a National Institute for Health Research Clinical Lectureship at St. George’s, University of London (CL-2020-16-001). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. This research was funded by United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7 to DG). For the purpose of open access, SB has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission. Funding Information: CDA has received sponsored research support from the American Heart Association, Massachusetts General Hospital, and Bayer AG, and has consulted for ApoPharma. JMMH is employed by Novo Nordisk. TGR, GKH, and DG are employed part-time by Novo Nordisk. DG is an Editorial Board Member of BMC Medicine; he had no role in the handling or peer review of the manuscript. The remaining authors have no conflicts of interest to declare. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - C-reactive protein
KW - Cardiovascular disease
KW - Cytokines
KW - Human genetics
KW - Inflammation
KW - Interleukin-6
KW - Mendelian randomization
UR - http://www.scopus.com/inward/record.url?scp=85135821487&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12916-022-02446-6
DO - https://doi.org/10.1186/s12916-022-02446-6
M3 - Article
C2 - 35948913
SN - 1464-2662
VL - 20
JO - BMC medicine
JF - BMC medicine
IS - 1
M1 - 245
ER -