Author + information
- Fabian Eichelmann, MSc,
- Matthias B. Schulze, MPH, DrPH,
- Clemens Wittenbecher, MSc, PhD,
- Juliane Menzel, MSc, PhD,
- Cornelia Weikert, MPH, MD,
- Romina di Giuseppe, PhD,
- Ronald Biemann, PhD,
- Berend Isermann, MD,
- Andreas Fritsche, MD,
- Heiner Boeing, MSc, PhD and
- Krasimira Aleksandrova, MPH, PhD∗ (, )@unipotsdam@Leibniz_DIfE
- ↵∗Senior Scientist Group Nutrition, Immunity and Metabolism, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
Immune-inflammatory pathways have been increasingly implicated in the pathogenesis of atherosclerosis and associated cardiovascular outcomes (1). Novel inflammatory biomarkers may help in better understanding these links. Chemerin is a recently discovered chemoattractant protein involved in the attraction of immune cells to sites of tissue damage including endothelium and smooth muscle (2). Elevated chemerin concentrations in blood circulation have been described in relation to metabolic risk factors and cardiovascular disease risk (3,4). However, prospective studies assessing whether elevated circulating chemerin precedes chronic disease development have been lacking. We therefore aimed to evaluate the association between circulating chemerin concentrations and risk of myocardial infarction (MI), stroke, and type 2 diabetes (T2D) using data from the EPIC (European Prospective Investigation into Cancer and Nutrition)-Potsdam cohort (N = 27,548). Chemerin was measured in plasma using sandwich–enzyme-linked immunosorbent assays (Biovendor, Brno, Czech Republic) in a random subsample (N exclusions = 2,342 for cardiovascular diseases [CVD] and 2,248 for T2D) and all incident MI and stroke cases. Incident cases (MI = 254, stroke = 241, T2D = 119) were identified via active follow-up and validated through standardized forms filled in by the participant’s treating or study physician. Participants with a prior diagnosis of heart failure, MI, or stroke (for T2D analyses also prevalent T2D) were excluded from the statistical analyses. Additional metabolic biomarkers (i.e., high-sensitivity C-reactive protein [hsCRP], lipoprotein fractions, triglycerides, glycated hemoglobin, fetuin-A, creatinine, γ-glutamyl transferase, alanine transaminase, and uric acid) were measured by ADVIA 1650 analyzer (Siemens Medical Solutions, Erlangen, Germany). Adiponectin was measured with an enzyme-linked immunosorbent assay. The study protocol was approved by the Medical Society of the State of Brandenburg, Germany, and all participants provided written informed consent before study enrollment (5).
The median chemerin concentration at study baseline was 150.4 ng/ml and ranged from 50.0 to 368.5 ng/ml. Participants who developed MI, stroke, or T2D during follow-up had higher concentrations (MI 171.4 ng/ml; stroke 164.3 ng/ml; T2D 173.2 ng/ml). In multivariable Cox proportional hazards models adjusted for age, sex, education, lifestyle factors, prevalent diabetes, hypertension and hyperlipidemia, and medication use, chemerin was strongly positively associated with MI, stroke, and T2D (hazard ratio [HR] quartile 4 vs. quartile 1: 3.13; 95% confidence interval [CI]: 1.91 to 5.11; 1.75; 95% CI: 1.08 to 2.81; and HR quartile 4 vs. quartile 1: 3.57; 95% CI: 1.75 to 7.28, respectively). Further adjustment for body mass index and waist circumference did not substantially alter the risk estimates for MI (HR quartile 4 vs. quartile 1: 3.17; 95% CI: 1.93 to 5.21) and stroke (HR quartile 4 vs. quartile 1: 1.94; 95% CI: 1.19 to 3.16), whereas the association with T2D was markedly attenuated (HR quartile 4 vs. quartile 1: 1.70; 95% CI: 0.83 to 3.50). The shapes of the associations in cubic spline regression models with and without adjustment for body mass index and waist circumference are presented in Figure 1. Overall, neither of the models revealed deviation from linearity, and a clear dose-response trend could be observed. Additional adjustment for metabolic biomarkers and hsCRP did not alter the overall results (data not shown).
This is the first prospective cohort study showing a strong positive association between chemerin and CVD independent of established risk factors. In case of T2D, a strong positive association was also found, though substantial proportion of it was explained by body mass index and waist circumference. In summary, current findings support the role of immune-inflammatory pathways in the development of CVD and suggest chemerin as an important disease risk marker.
Please note: The study was supported by the Federal Ministry of Science, Germany, (grant 01 EA 9401) and the European Union (grant SOC 95201408 05 F02) for the recruitment phase of the EPIC-Potsdam study, and by the German Cancer Aid (Grant 70-2488-Ha I) and the European Community (Grant SOC 98200769 05 F02) for the follow-up of the EPIC-Potsdam study. This work was also partly supported by the German Research Foundation (grant AL 1784/3-1), which funded the research position of Dr. Aleksandrova for the time of study conduct and analysis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation