The association between plasma proteomics and incident cardiovascular disease identifies MMP-12 as a promising cardiovascular risk marker in patients with chronic kidney disease. (August 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Atherosclerosis. Volume 307(2020)
• Page Start: 11
• Page End: 15
• Publication Date: 2020-08
• Subjects: Proteomics -- Chronic kidney disease -- Community-based cohorts -- Cardiovascular risk marker -- Major adverse cardiovascular events; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2020.06.013
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: 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. Methods: 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. Results: 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). Conclusions: Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD. Graphical abstract: Image 1 Highlights: 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.