A plasma proteogenomic signature for fibromuscular dysplasia

Jeffrey W. Olin; Antonio F. Di Narzo; Valentina D'Escamard; Daniella Kadian-Dodov; Haoxiang Cheng; Adrien Georges; Annette King; Allison Thomas; Temo Barwari; Katherine C. Michelis; Rihab Bouchareb; Emir Bander; Anelechi Anyanwu; Paul Stelzer; Farzan Filsoufi; Sander Florman; Mete Civelek; Stephanie Debette; Xavier Jeunemaitre; Johan L.M. Björkegren; Manuel Mayr; Nabila Bouatia-Naji; Ke Hao; Jason C. Kovacic

doi:10.1093/cvr/cvz219

A plasma proteogenomic signature for fibromuscular dysplasia

Jeffrey W. Olin, Antonio F. Di Narzo, Valentina D'Escamard, Daniella Kadian-Dodov, Haoxiang Cheng, Adrien Georges, Annette King, Allison Thomas, Temo Barwari, Katherine C. Michelis, Rihab Bouchareb, Emir Bander, Anelechi Anyanwu, Paul Stelzer, Farzan Filsoufi, Sander Florman, Mete Civelek, Stephanie Debette, Xavier Jeunemaitre, Johan L.M. BjörkegrenManuel Mayr, Nabila Bouatia-Naji, Ke Hao, Jason C. Kovacic^*

^*Corresponding author for this work

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

27 Citations (Scopus)

Abstract

Aims: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and results: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (N_cases = 90, N_controls = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (N_cases = 23, N_controls = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (N_cases = 506, N_controls = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. Conclusion: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

Original language	English
Pages (from-to)	63-77
Number of pages	15
Journal	Cardiovascular Research
Volume	116
Issue number	1
DOIs	https://doi.org/10.1093/cvr/cvz219
Publication status	Published - 1 Jan 2020

Keywords

CD2AP
Fibromuscular dysplasia
Plasma protein
Proteomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/cvr/cvz219

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Olin, J. W., Di Narzo, A. F., D'Escamard, V., Kadian-Dodov, D., Cheng, H., Georges, A., King, A., Thomas, A., Barwari, T., Michelis, K. C., Bouchareb, R., Bander, E., Anyanwu, A., Stelzer, P., Filsoufi, F., Florman, S., Civelek, M., Debette, S., Jeunemaitre, X., ... Kovacic, J. C. (2020). A plasma proteogenomic signature for fibromuscular dysplasia. Cardiovascular Research, 116(1), 63-77. https://doi.org/10.1093/cvr/cvz219

@article{48cd88d1586c4b04a28d38c5e47b5710,

title = "A plasma proteogenomic signature for fibromuscular dysplasia",

abstract = "Aims: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and results: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. Conclusion: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.",

keywords = "CD2AP, Fibromuscular dysplasia, Plasma protein, Proteomics",

author = "Olin, {Jeffrey W.} and {Di Narzo}, {Antonio F.} and Valentina D'Escamard and Daniella Kadian-Dodov and Haoxiang Cheng and Adrien Georges and Annette King and Allison Thomas and Temo Barwari and Michelis, {Katherine C.} and Rihab Bouchareb and Emir Bander and Anelechi Anyanwu and Paul Stelzer and Farzan Filsoufi and Sander Florman and Mete Civelek and Stephanie Debette and Xavier Jeunemaitre and Bj{\"o}rkegren, {Johan L.M.} and Manuel Mayr and Nabila Bouatia-Naji and Ke Hao and Kovacic, {Jason C.}",

year = "2020",

month = jan,

day = "1",

doi = "10.1093/cvr/cvz219",

language = "English",

volume = "116",

pages = "63--77",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "1",

}

Olin, JW, Di Narzo, AF, D'Escamard, V, Kadian-Dodov, D, Cheng, H, Georges, A, King, A, Thomas, A, Barwari, T, Michelis, KC, Bouchareb, R, Bander, E, Anyanwu, A, Stelzer, P, Filsoufi, F, Florman, S, Civelek, M, Debette, S, Jeunemaitre, X, Björkegren, JLM, Mayr, M, Bouatia-Naji, N, Hao, K & Kovacic, JC 2020, 'A plasma proteogenomic signature for fibromuscular dysplasia', Cardiovascular Research, vol. 116, no. 1, pp. 63-77. https://doi.org/10.1093/cvr/cvz219

TY - JOUR

T1 - A plasma proteogenomic signature for fibromuscular dysplasia

AU - Olin, Jeffrey W.

AU - Di Narzo, Antonio F.

AU - D'Escamard, Valentina

AU - Kadian-Dodov, Daniella

AU - Cheng, Haoxiang

AU - Georges, Adrien

AU - King, Annette

AU - Thomas, Allison

AU - Barwari, Temo

AU - Michelis, Katherine C.

AU - Bouchareb, Rihab

AU - Bander, Emir

AU - Anyanwu, Anelechi

AU - Stelzer, Paul

AU - Filsoufi, Farzan

AU - Florman, Sander

AU - Civelek, Mete

AU - Debette, Stephanie

AU - Jeunemaitre, Xavier

AU - Björkegren, Johan L.M.

AU - Mayr, Manuel

AU - Bouatia-Naji, Nabila

AU - Hao, Ke

AU - Kovacic, Jason C.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Aims: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and results: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. Conclusion: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

AB - Aims: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and results: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. Conclusion: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

KW - CD2AP

KW - Fibromuscular dysplasia

KW - Plasma protein

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=85076876769&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvz219

DO - 10.1093/cvr/cvz219

M3 - Article

C2 - 31424497

AN - SCOPUS:85076876769

SN - 0008-6363

VL - 116

SP - 63

EP - 77

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 1

ER -

A plasma proteogenomic signature for fibromuscular dysplasia

Abstract

Keywords

UN SDGs

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