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

Joao Pedro Ferreira; Anne Pizard; Jean-Loup Machu; Emmanuel Bresso; Hans-Peter Brunner-La Rocca; Nicolas Girerd; Celine Leroy; Arantxa Gonzalez; Javier Diez; Stephane Heymans; Marie-Dominique Devignes; Patrick Rossignol; Faiez Zannad; FIBRO-TARGETS investigators

doi:10.1007/s00392-019-01480-4

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

Joao Pedro Ferreira^*, Anne Pizard, Jean-Loup Machu, Emmanuel Bresso, Hans-Peter Brunner-La Rocca, Nicolas Girerd, Celine Leroy, Arantxa Gonzalez, Javier Diez, Stephane Heymans, Marie-Dominique Devignes, Patrick Rossignol, Faiez Zannad, FIBRO-TARGETS investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

[GRAPHICS]

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Original language	English
Pages (from-to)	22-33
Number of pages	12
Journal	Clinical research in cardiology
Volume	109
Issue number	1
DOIs	https://doi.org/10.1007/s00392-019-01480-4
Publication status	Published - Jan 2020

Keywords

Cardiovascular diseases
Phenotypes
Proteomics
LASSO
Decision tree
Complex networks
STEM-CELL FACTOR
DIABETES-MELLITUS
BLOOD-PRESSURE
TASK-FORCE
DISEASE
RISK
DATABASE
VARIANT
RATIONALE
UPDATE

Access to Document

10.1007/s00392-019-01480-4

Cite this

Ferreira, J. P., Pizard, A., Machu, J.-L., Bresso, E., Brunner-La Rocca, H.-P., Girerd, N., Leroy, C., Gonzalez, A., Diez, J., Heymans, S., Devignes, M.-D., Rossignol, P., Zannad, F., & FIBRO-TARGETS investigators (2020). Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case-control analyses. Clinical research in cardiology, 109(1), 22-33. https://doi.org/10.1007/s00392-019-01480-4

@article{27cc3480f07f498fac7155e7357d6a5d,

title = "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 abstractPlasma 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.[GRAPHICS].",

keywords = "Cardiovascular diseases, Phenotypes, Proteomics, LASSO, Decision tree, Complex networks, STEM-CELL FACTOR, DIABETES-MELLITUS, BLOOD-PRESSURE, TASK-FORCE, DISEASE, RISK, DATABASE, VARIANT, RATIONALE, UPDATE",

author = "Ferreira, {Joao Pedro} and Anne Pizard and Jean-Loup Machu and Emmanuel Bresso and {Brunner-La Rocca}, Hans-Peter and Nicolas Girerd and Celine Leroy and Arantxa Gonzalez and Javier Diez and Stephane Heymans and Marie-Dominique Devignes and Patrick Rossignol and Faiez Zannad and {FIBRO-TARGETS investigators}",

note = "Funding Information: 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 Universit? d?Excellence???GEENAGE (ANR-15-IDEX-04-LUE) programs, and the Contrat de Plan Etat R?gion 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. Publisher Copyright: {\textcopyright} 2019, Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2020",

month = jan,

doi = "10.1007/s00392-019-01480-4",

language = "English",

volume = "109",

pages = "22--33",

journal = "Clinical research in cardiology",

issn = "1861-0684",

publisher = "Springer",

number = "1",

}

Ferreira, JP, Pizard, A, Machu, J-L, Bresso, E, Brunner-La Rocca, H-P, Girerd, N, Leroy, C, Gonzalez, A, Diez, J, Heymans, S, Devignes, M-D, Rossignol, P, Zannad, F & FIBRO-TARGETS investigators 2020, 'Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case-control analyses', Clinical research in cardiology, vol. 109, no. 1, pp. 22-33. https://doi.org/10.1007/s00392-019-01480-4

TY - JOUR

T1 - Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes

T2 - the FIBRO-TARGETS case-control analyses

AU - Ferreira, Joao Pedro

AU - Pizard, Anne

AU - Machu, Jean-Loup

AU - Bresso, Emmanuel

AU - Brunner-La Rocca, Hans-Peter

AU - Girerd, Nicolas

AU - Leroy, Celine

AU - Gonzalez, Arantxa

AU - Diez, Javier

AU - Heymans, Stephane

AU - Devignes, Marie-Dominique

AU - Rossignol, Patrick

AU - Zannad, Faiez

AU - FIBRO-TARGETS investigators

N1 - Funding Information: 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 Universit? d?Excellence???GEENAGE (ANR-15-IDEX-04-LUE) programs, and the Contrat de Plan Etat R?gion 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. Publisher Copyright: © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2020/1

Y1 - 2020/1

N2 - 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 abstractPlasma 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.[GRAPHICS].

AB - 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 abstractPlasma 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.[GRAPHICS].

KW - Cardiovascular diseases

KW - Phenotypes

KW - Proteomics

KW - LASSO

KW - Decision tree

KW - Complex networks

KW - STEM-CELL FACTOR

KW - DIABETES-MELLITUS

KW - BLOOD-PRESSURE

KW - TASK-FORCE

KW - DISEASE

KW - RISK

KW - DATABASE

KW - VARIANT

KW - RATIONALE

KW - UPDATE

U2 - 10.1007/s00392-019-01480-4

DO - 10.1007/s00392-019-01480-4

M3 - Article

C2 - 31062082

SN - 1861-0684

VL - 109

SP - 22

EP - 33

JO - Clinical research in cardiology

JF - Clinical research in cardiology

IS - 1

ER -