Author + information
- Nicholas K. Brownell, MD,
- Amit Khera, MD, MSc,
- James A. de Lemos, MD,
- Colby R. Ayers, MS and
- Anand Rohatgi, MD, MSCS∗ ()
- ↵∗Address for correspondence:
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8830
Peptidoglycan recognition protein-1 (PGLYRP-1) is a secreted, circulating protein that binds peptidoglycan and promotes inflammation through the activation of innate immune mechanisms (1). PGLYRP-1 is found almost exclusively in the secretory granules of neutrophils and eosinophils, and its target, peptidoglycan, is a bacterial wall constituent known to be present in human atheroma (1,2). However, few data are available regarding the potential role of PGLYRP-1 in vascular inflammation. We previously showed that circulating PGLYRP-1 levels were associated with prevalent subclinical atherosclerosis in humans as evidenced by coronary artery calcium and abdominal aortic wall thickness (3). More recently, a blood transcriptome study identified PGLYRP-1 in patients with acute coronary syndromes (4). These associations with prevalent subclinical and acute atherosclerotic disease suggest a potential role for PGLYRP-1 as an atherosclerosis biomarker. Therefore, we investigated the association between baseline PGLYRP-1 levels and incident cardiovascular events in a multiethnic population free of cardiovascular disease (CVD).
The Dallas Heart Study is a probability-based population sample of Dallas County residents, aged 30 to 65, with intentional oversampling of self-identified African Americans (3). Of the 3,557 participants who provided blood, 3,222 had PGLYRP-1 measured by a proprietary sandwich immunoassay (intraplate CV, 6%; interplate CV, 7%) at Biosite, Inc. in San Diego, California (now Alere, Inc., Waltham, Massachusetts). Of these 3,222, a total of 2,443 were free of CVD at baseline, had full risk factor ascertainment, and had complete follow-up for atherosclerotic CVD (ASCVD) events, defined as nonfatal myocardial infarction, stroke, coronary revascularization, and cardiovascular death (5). Cox proportional hazards models were used to assess the association between PGLYRP-1 quartiles and ASCVD events adjusted for age, sex, race, hypertension (including antihypertensive medication use), diabetes (including hypoglycemic medication use), smoking, hypercholesterolemia (including statin therapy), low high-density lipoprotein cholesterol, and body mass index. Sensitivity analyses were performed analyzing PGLYRP-1 by the optimal sex/race-specific threshold determined by receiver operating characteristic curve and as a continuous variable per 1 SD change in log-PGLYRP-1.
In this cohort of 2,443 participants, the mean age was 43.8 ± 10.0 years, with 57% women and 49% African Americans. A total of 162 first ASCVD events occurred over a mean follow-up of 10 years. In unadjusted models, increasing quartiles of PGLYRP-1 were associated with increased incidence of ASCVD events (log-rank p value < 0.0001) (Figure 1A). The top versus bottom quartile of PGLYRP-1 was associated with a >3-fold increased risk of ASCVD (hazard ratio [HR]: 3.43; 95% confidence interval [CI]: 2.15 to 5.47; p < 0.0001), remaining significant in adjusted multivariate models (HR: 2.14; 95% CI: 1.33 to 3.47; p = 0.002). The results were similar when PGLYRP-1 was dichotomized by receiver operating characteristic–determined threshold (80th percentile; Figure 1B) and when analyzed as a continuous variable (adjusted HR per SD: 1.36; 95% CI: 1.19 to 1.56; p < 0.0001). Serial adjustment for renal function (estimated glomerular filtration rate) and prevalent coronary artery calcium did not alter the findings. Exploratory analyses revealed a magnified association between PGLYRP-1 and ASCVD in participants with elevated high-sensitivity C-reactive protein (hs-CRP) (HR Q4 vs. Q1 among hs-CRP ≥3 mg/l: 3.39, 95% CI: 1.61 to 7.12 vs. among hs-CRP <3 mg/l: 1.01, 95% CI: 0.56 to 2.13, pinteraction = 0.09; HR elevated PGLYRP-1 by receiver operating characteristic among hs-CRP ≥3 mg/l: 2.40, 95% CI: 1.56 to 3.70 vs. among hs-CRP <3 mg/l: 1.82, 95% CI: 1.03 to 3.22, pinteraction = 0.0001). In linear regression models evaluating PGLYRP-1 as the dependent variable, 6 inflammatory markers (hs-CRP, interleukin-6, soluble CD40 ligand, soluble endothelial cell-selective adhesion molecule, monocyte-chemoattractant protein-1, and Cystatin C) accounted for 30% of the variance in PGLYRP-1. Adjustment for inflammatory markers did not alter the findings.
In a large population-based cohort free of CVD, increased circulating PGLYRP-1 levels at baseline were independently associated with an increased risk of first ASCVD events, suggesting that the biological processes reflected by elevated PGLYRP-1 may be related to the development of clinical ASCVD. The observation of potential effect modification by baseline inflammation, as reflected by stronger associations of PGLYRP-1 with ASCVD in participants with elevated hs-CRP, suggests that PGLYRP-1 may reflect the link between inflammation, accelerated atherosclerotic plaque, and increased cardiovascular risk. Further studies are warranted to determine the specific role of PGLYRP-1 in mammalian models of atherosclerosis and whether PGLYRP-1 could serve as a clinically useful ASCVD risk marker and therapeutic target.
Please note: The Dallas Heart Study was funded by the Donald W. Reynolds Foundation and was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award UL1TR001105. PGLYRP-1 measurements were provided by Biosite, Inc. (now Alere Inc., Waltham, Massachusetts). Dr. Rohatgi is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award K08HL118131. The funding agencies had no role in the design and conduct of the study and no role in the collection, analysis, and interpretation of the data, nor in the preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Heart, Lung, and Blood Institute or Alere, Inc. Dr. de Lemos has received grant support and consulting income from Abbott Diagnostics and Roche Diagnostics. Dr. Rohatgi has received a research grant from Merck; serves on the advisory board for Cleveland HeartLab; and is a consultant to CSL Limited and Vascular Strategies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2016 American College of Cardiology Foundation