Association of Circulating Monocyte Chemoattractant Protein-1 Levels with Cardiovascular Mortality: A Meta-analysis of Population-Based Studies

Marios K. Georgakis, James A. De Lemos, Colby Ayers, Biqi Wang, Harry Björkbacka, Tiberiu A. Pana, Barbara Thorand, Caroline Sun, Lana Fani, Rainer Malik, Josée Dupuis, Gunnar Engström, Marju Orho-Melander, Olle Melander, S. Matthijs Boekholdt, Astrid Zierer, Mohamed A. Elhadad, Wolfgang Koenig, Christian Herder, Ron C. HoogeveenMaryam Kavousi, Christie M. Ballantyne, Annette Peters, Phyo K. Myint, Jan Nilsson, Emelia J. Benjamin, Martin Dichgans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

Abstract

Importance: Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored. Objective: To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population. Data Sources and Selection: Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points. Data Extraction and Synthesis: Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses. Main Outcomes and Measures: Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes). Results: The meta-analysis included 7 cohort studies involving 21401 individuals (mean [SD] age, 53.7 [10.2] years; 10012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P =.01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P =.02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P <.001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein. Conclusions and Relevance: Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease..

Original languageEnglish
Pages (from-to)587-592
Number of pages6
JournalJAMA Cardiology
Volume6
Issue number5
Early online date4 Nov 2020
DOIs
Publication statusPublished - May 2021

Bibliographical note

Funding/Support:
Dr Georgakis has received
funding from the Onassis Foundation and the
German Academic Exchange Service. The
Atherosclerosis Risk in Communities study has been
funded in whole or in part with federal funds from
the National Heart, Lung, and Blood Institute,
National Institutes of Health, Department of Health
and Human Services, (contracts
HHSN268201700001I, HHSN268201700002I,
HHSN268201700003I, HHSN268201700005I,
and HHSN268201700004I). The Dallas Heart
Study was funded by a grant from the Donald W.
Reynolds Foundation. The European Prospective
Investigation Into Cancer in Norfolk Prospective
Population study has received funding from the
Medical Research Council (grants MR/N003284/1
and MC-UU_12015/1) and Cancer Research UK
(grant C864/A14136). The Framingham Heart Study
is conducted and supported by the National Heart,
Lung, and Blood Institute in collaboration with
Boston University (contracts N01-HC-25195,
HHSN268201500001I, and 75N92019D00031)
and is additionally supported by grants from the
National Institute of Aging and the National
Institute of Neurological Disorders and Stroke
(grants RO1 HL 064753, RO1 HL076784, and R01
AG028321). The Monitoring of Trends and
Determinants in Cardiovascular Disease–
Kooperative Gesundheitsforschung in der Region
Augsburg study was initiated and financed by the
Helmholtz Zentrum München–German Research
Center for Environmental Health, which is funded
by the German Federal Ministry of Education and
Research and the state of Bavaria. Support for the
establishment of the case-cohort study and MCP-1
measurements was obtained through a grant from
the German Research Foundation (grants TH-784/
2-1 and TH-784/2-2) and additional funds provided
by the University of Ulm, the Federal Ministry of
Health, the Ministry of Innovation, Science,
Research and Technology of the state North Rhine–
Westphalia. Data analysis was supported by funding
from the Helmholtz Alliance “Aging and Metabolic
Programming.” The German Diabetes Center is
funded by the German Federal Ministry of Health,
the Ministry of Culture and Science of the state of
North Rhine–Westphalia, and grants from the
Federal Ministry of Education and Research. The
Malmö Diet and Cancer Study–Cardiovascular
Subcohort study has been supported with funding
from the Swedish Research Council, Swedish Heart
and Lung Foundations, and the Swedish
Foundation for Strategic Research. This project has
received funding from the European Union’s
Horizon 2020 research and innovation programme
(grant 666881), SVDs@target (to Dr Dichgans;
grant 667375), CoSTREAM (to Dr Dichgans); the
German Research Foundation as part of the Munich
Cluster for Systems Neurology (grant EXC 2145
SyNergy, ID 390857198) and the Collaborative
Research Center 1123 (B3; to Dr Dichgans); the
Corona Foundation (to Dr Dichgans); the Fondation
Leducq (Transatlantic Network of Excellence on the
Pathogenesis of Small Vessel Disease of the Brain;
to Dr Dichgans); the e:Med program
(e:AtheroSysMed; to Dr Dichgans) and the
European Union project CVgenes@target (project
FP7/2007-2103; grant agreement number
Health-F2-2013-601456; to Dr Dichgans).

Publisher Copyright: © 2021 American Medical Association. All rights reserved.

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