The association between plasma proteomics and incident cardiovascular disease identifies MMP-12 as a promising cardiovascular risk marker in patients with chronic kidney disease

• Published in: Atherosclerosis Vol. 307; pp. 11 - 15
• Main Authors: Feldreich, Tobias, Nowak, Christoph, Carlsson, Axel C., Östgren, Carl-Johan, Nyström, Fredrik H., Sundström, Johan, Carrero-Roig, Juan-Jesus, Leppert, Jerzy, Hedberg, Pär, Giedraitis, Vilmantas, Lind, Lars, Cordeiro, Antonio, Ärnlöv, Johan
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-08-2020
• Subjects: Biomarkers; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - epidemiology; Cardiovascular risk marker; Chronic kidney disease; Community-based cohorts; Fibroblast Growth Factor-23; Health and Welfare; Heart Disease Risk Factors; Humans; Hälsa och välfärd; Major adverse cardiovascular events; Matrix Metalloproteinase 12; Medicin och hälsovetenskap; Proteomics; Renal Insufficiency, Chronic - diagnosis; Renal Insufficiency, Chronic - epidemiology; Risk Factors; Cardiovascular risk marker; Chronic kidney disease; Major adverse cardiovascular events; Community-based cohorts; Proteomics
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2020.06.013

Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD.
Individuals with CKD stages 3–5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample.
In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 ± 2.9 years (range 0.005–12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean ± SD change of 2.9 ± 1.2 years (range 0.1–4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07–1.75), p = 0.013).
Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.
[Display omitted]
•Plasma MMP-12 as a potential cardiovascular risk marker in patients with chronic kidney disease (CKD) using a multiplex proteomics method.•Higher levels of MMP-12 are associated with incident CKD in multivariable models adjusted for age, sex, kidney function, and cardiovascular risk factors.•Additional exploration of the utility of proteomic profiling in the clinical setting of patients with CKD is needed.