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Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case–control analyses

Abstract

Background

Hypertension, obesity and diabetes are major and potentially modifiable “risk factors” for cardiovascular diseases. Identification of biomarkers specific to these risk factors may help understanding the underlying pathophysiological pathways, and developing individual treatment.

Methods

The FIBRO-TARGETS (targeting cardiac fibrosis for heart failure treatment) consortium has merged data from 12 patient cohorts in 1 common database of > 12,000 patients. Three mutually exclusive main phenotypic groups were identified (“cases”): (1) “hypertensive”; (2) “obese”; and (3) “diabetic”; age–sex matched in a 1:2 proportion with “healthy controls” without any of these phenotypes. Proteomic associations were studied using a biostatistical method based on LASSO and confronted with machine-learning and complex network approaches.

Results

The case:control distribution by each cardiovascular phenotype was hypertension (50:100), obesity (50:98), and diabetes (36:72). Of the 86 studied proteins, 4 were found to be independently associated with hypertension: GDF-15, LEP, SORT-1 and FABP-2; 3 with obesity: CEACAM-8, LEP and PRELP; and 4 with diabetes: GDF-15, REN, CXCL-1 and SCF. GDF-15 (hypertension + diabetes) and LEP (hypertension + obesity) are shared by 2 different phenotypes. A machine-learning approach confirmed GDF-15, LEP and SORT-1 as discriminant biomarkers for the hypertension group, and LEP plus PRELP for the obesity group. Complex network analyses provided insight on the mechanisms underlying these disease phenotypes where fibrosis may play a central role.

Conclusion

Patients with “mutually exclusive” phenotypes display distinct bioprofiles that might underpin different biological pathways, potentially leading to fibrosis.

Graphic abstract

Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case–control analyses. Patients with “mutually exclusive” phenotypes (blue: obesity, hypertension and diabetes) display distinct protein bioprofiles (green: decreased expression; red: increased expression) that might underpin different biological pathways (orange arrow), potentially leading to fibrosis.

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Acknowledgements

JF, AP, JLM, PR, NG, MD D, EB and FZ are supported by the French National Research Agency Fighting Heart Failure (ANR-15-RHU-0004), by the French PIA project « Lorraine Université d’Excellence » GEENAGE (ANR-15-IDEX-04-LUE) programs, and the Contrat de Plan Etat Région Lorraine and FEDER IT2MP. The authors thank the CRB Lorrain biobank for handling biosamples. The research leading to these results has received funding from the European Union Commission’s Seventh Framework programme under Grant agreement no. 602904 (FIBROTARGETS) and No. 261409 (MEDIA). SH acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, and CVON She-PREDICTS, 2017-21. This research is co-financed as a PPP-allowance Research and Innovation by the Ministry of Economic Affairs within Top Sector Life sciences & Health in the Netherlands.

Funding

This work was funded through the European Commission Seventh Framework Programme (FIBRO-TARGETS project grant #602904 HEALTH-2013-602904) and the REBIRTH Excellence Cluster, Hannover Medical School.

Author information

Correspondence to João Pedro Ferreira.

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Conflict of interest

All authors are actively involved in the FIBROTARGETS consortium.

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Ferreira, J., Pizard, A., Machu, J. et al. Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case–control analyses. Clin Res Cardiol 109, 22–33 (2020) doi:10.1007/s00392-019-01480-4

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Keywords

  • Cardiovascular diseases
  • Phenotypes
  • Proteomics
  • LASSO
  • Decision tree
  • Complex networks