Jeffrey W Olin1, Antonio F Di Narzo2, Valentina d'Escamard1, Daniella Kadian-Dodov1, Haoxiang Cheng2, Adrien Georges3,4, Annette King1, Allison Thomas1, Temo Barwari5, Katherine C Michelis1, Rihab Bouchareb1, Emir Bander1, Anelechi Anyanwu6, Paul Stelzer6, Farzan Filsoufi6, Sander Florman7, Mete Civelek8, Stephanie Debette9,10, Xavier Jeunemaitre3,4,11, Johan L M Björkegren2,12, Manuel Mayr1,5, Nabila Bouatia-Naji3,4, Ke Hao2, Jason C Kovacic1. 1. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. 2. Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. INSERM, UMR970 Paris Cardiovascular Research Center (PARCC), Paris, France. 4. Paris-Descartes University, Sorbonne Paris Cité, Paris 75006, France. 5. King's British Heart Foundation Centre, King's College London, London, UK. 6. Department of Cardiovascular Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 7. Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. 9. Bordeaux Population Health Research Centre, INSERM U1219, University of Bordeaux, Bordeaux, France. 10. Memory Clinic, Department of Neurology and Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France. 11. Assistance Publique-Hôpital De Paris, Department of Genetics and Referral Center for Rare Vascular Diseases, Hôpital Européen Georges Pompidou, Paris, F-75015, France. 12. Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Adam C Naj; Gyungah Jun; Gary W Beecham; Li-San Wang; Badri Narayan Vardarajan; Jacqueline Buros; Paul J Gallins; Joseph D Buxbaum; Gail P Jarvik; Paul K Crane; Eric B Larson; Thomas D Bird; Bradley F Boeve; Neill R Graff-Radford; Philip L De Jager; Denis Evans; Julie A Schneider; Minerva M Carrasquillo; Nilufer Ertekin-Taner; Steven G Younkin; Carlos Cruchaga; John S K Kauwe; Petra Nowotny; Patricia Kramer; John Hardy; Matthew J Huentelman; Amanda J Myers; Michael M Barmada; F Yesim Demirci; Clinton T Baldwin; Robert C Green; Ekaterina Rogaeva; Peter St George-Hyslop; Steven E Arnold; Robert Barber; Thomas Beach; Eileen H Bigio; James D Bowen; Adam Boxer; James R Burke; Nigel J Cairns; Chris S Carlson; Regina M Carney; Steven L Carroll; Helena C Chui; David G Clark; Jason Corneveaux; Carl W Cotman; Jeffrey L Cummings; Charles DeCarli; Steven T DeKosky; Ramon Diaz-Arrastia; Malcolm Dick; Dennis W Dickson; William G Ellis; Kelley M Faber; Kenneth B Fallon; Martin R Farlow; Steven Ferris; Matthew P Frosch; Douglas R Galasko; Mary Ganguli; Marla Gearing; Daniel H Geschwind; Bernardino Ghetti; John R Gilbert; Sid Gilman; Bruno Giordani; Jonathan D Glass; John H Growdon; Ronald L Hamilton; Lindy E Harrell; Elizabeth Head; Lawrence S Honig; Christine M Hulette; Bradley T Hyman; Gregory A Jicha; Lee-Way Jin; Nancy Johnson; Jason Karlawish; Anna Karydas; Jeffrey A Kaye; Ronald Kim; Edward H Koo; Neil W Kowall; James J Lah; Allan I Levey; Andrew P Lieberman; Oscar L Lopez; Wendy J Mack; Daniel C Marson; Frank Martiniuk; Deborah C Mash; Eliezer Masliah; Wayne C McCormick; Susan M McCurry; Andrew N McDavid; Ann C McKee; Marsel Mesulam; Bruce L Miller; Carol A Miller; Joshua W Miller; Joseph E Parisi; Daniel P Perl; Elaine Peskind; Ronald C Petersen; Wayne W Poon; Joseph F Quinn; Ruchita A Rajbhandary; Murray Raskind; Barry Reisberg; John M Ringman; Erik D Roberson; Roger N Rosenberg; Mary Sano; Lon S Schneider; William Seeley; Michael L Shelanski; Michael A Slifer; Charles D Smith; Joshua A Sonnen; Salvatore Spina; Robert A Stern; Rudolph E Tanzi; John Q Trojanowski; Juan C Troncoso; Vivianna M Van Deerlin; Harry V Vinters; Jean Paul Vonsattel; Sandra Weintraub; Kathleen A Welsh-Bohmer; Jennifer Williamson; Randall L Woltjer; Laura B Cantwell; Beth A Dombroski; Duane Beekly; Kathryn L Lunetta; Eden R Martin; M Ilyas Kamboh; Andrew J Saykin; Eric M Reiman; David A Bennett; John C Morris; Thomas J Montine; Alison M Goate; Deborah Blacker; Debby W Tsuang; Hakon Hakonarson; Walter A Kukull; Tatiana M Foroud; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Gerard D Schellenberg Journal: Nat Genet Date: 2011-04-03 Impact factor: 38.330
Authors: Paul Hollingworth; Denise Harold; Rebecca Sims; Amy Gerrish; Jean-Charles Lambert; Minerva M Carrasquillo; Richard Abraham; Marian L Hamshere; Jaspreet Singh Pahwa; Valentina Moskvina; Kimberley Dowzell; Nicola Jones; Alexandra Stretton; Charlene Thomas; Alex Richards; Dobril Ivanov; Caroline Widdowson; Jade Chapman; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K Lupton; Carol Brayne; David C Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kristelle S Brown; Peter A Passmore; David Craig; Bernadette McGuinness; Stephen Todd; Clive Holmes; David Mann; A David Smith; Helen Beaumont; Donald Warden; Gordon Wilcock; Seth Love; Patrick G Kehoe; Nigel M Hooper; Emma R L C Vardy; John Hardy; Simon Mead; Nick C Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Eckart Rüther; Britta Schürmann; Reiner Heun; Heike Kölsch; Hendrik van den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Frölich; Harald Hampel; John Gallacher; Michael Hüll; Dan Rujescu; Ina Giegling; Alison M Goate; John S K Kauwe; Carlos Cruchaga; Petra Nowotny; John C Morris; Kevin Mayo; Kristel Sleegers; Karolien Bettens; Sebastiaan Engelborghs; Peter P De Deyn; Christine Van Broeckhoven; Gill Livingston; Nicholas J Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Ammar Al-Chalabi; Christopher E Shaw; Magda Tsolaki; Andrew B Singleton; Rita Guerreiro; Thomas W Mühleisen; Markus M Nöthen; Susanne Moebus; Karl-Heinz Jöckel; Norman Klopp; H-Erich Wichmann; V Shane Pankratz; Sigrid B Sando; Jan O Aasly; Maria Barcikowska; Zbigniew K Wszolek; Dennis W Dickson; Neill R Graff-Radford; Ronald C Petersen; Cornelia M van Duijn; Monique M B Breteler; M Arfan Ikram; Anita L DeStefano; Annette L Fitzpatrick; Oscar Lopez; Lenore J Launer; Sudha Seshadri; Claudine Berr; Dominique Campion; Jacques Epelbaum; Jean-François Dartigues; Christophe Tzourio; Annick Alpérovitch; Mark Lathrop; Thomas M Feulner; Patricia Friedrich; Caterina Riehle; Michael Krawczak; Stefan Schreiber; Manuel Mayhaus; S Nicolhaus; Stefan Wagenpfeil; Stacy Steinberg; Hreinn Stefansson; Kari Stefansson; Jon Snaedal; Sigurbjörn Björnsson; Palmi V Jonsson; Vincent Chouraki; Benjamin Genier-Boley; Mikko Hiltunen; Hilkka Soininen; Onofre Combarros; Diana Zelenika; Marc Delepine; Maria J Bullido; Florence Pasquier; Ignacio Mateo; Ana Frank-Garcia; Elisa Porcellini; Olivier Hanon; Eliecer Coto; Victoria Alvarez; Paolo Bosco; Gabriele Siciliano; Michelangelo Mancuso; Francesco Panza; Vincenzo Solfrizzi; Benedetta Nacmias; Sandro Sorbi; Paola Bossù; Paola Piccardi; Beatrice Arosio; Giorgio Annoni; Davide Seripa; Alberto Pilotto; Elio Scarpini; Daniela Galimberti; Alexis Brice; Didier Hannequin; Federico Licastro; Lesley Jones; Peter A Holmans; Thorlakur Jonsson; Matthias Riemenschneider; Kevin Morgan; Steven G Younkin; Michael J Owen; Michael O'Donovan; Philippe Amouyel; Julie Williams Journal: Nat Genet Date: 2011-04-03 Impact factor: 38.330
Authors: Lasse Folkersen; Eric Fauman; Maria Sabater-Lleal; Rona J Strawbridge; Mattias Frånberg; Bengt Sennblad; Damiano Baldassarre; Fabrizio Veglia; Steve E Humphries; Rainer Rauramaa; Ulf de Faire; Andries J Smit; Philippe Giral; Sudhir Kurl; Elmo Mannarino; Stefan Enroth; Åsa Johansson; Sofia Bosdotter Enroth; Stefan Gustafsson; Lars Lind; Cecilia Lindgren; Andrew P Morris; Vilmantas Giedraitis; Angela Silveira; Anders Franco-Cereceda; Elena Tremoli; Ulf Gyllensten; Erik Ingelsson; Søren Brunak; Per Eriksson; Daniel Ziemek; Anders Hamsten; Anders Mälarstig Journal: PLoS Genet Date: 2017-04-03 Impact factor: 5.917
Authors: J C Lambert; C A Ibrahim-Verbaas; D Harold; A C Naj; R Sims; C Bellenguez; A L DeStafano; J C Bis; G W Beecham; B Grenier-Boley; G Russo; T A Thorton-Wells; N Jones; A V Smith; V Chouraki; C Thomas; M A Ikram; D Zelenika; B N Vardarajan; Y Kamatani; C F Lin; A Gerrish; H Schmidt; B Kunkle; M L Dunstan; A Ruiz; M T Bihoreau; S H Choi; C Reitz; F Pasquier; C Cruchaga; D Craig; N Amin; C Berr; O L Lopez; P L De Jager; V Deramecourt; J A Johnston; D Evans; S Lovestone; L Letenneur; F J Morón; D C Rubinsztein; G Eiriksdottir; K Sleegers; A M Goate; N Fiévet; M W Huentelman; M Gill; K Brown; M I Kamboh; L Keller; P Barberger-Gateau; B McGuiness; E B Larson; R Green; A J Myers; C Dufouil; S Todd; D Wallon; S Love; E Rogaeva; J Gallacher; P St George-Hyslop; J Clarimon; A Lleo; A Bayer; D W Tsuang; L Yu; M Tsolaki; P Bossù; G Spalletta; P Proitsi; J Collinge; S Sorbi; F Sanchez-Garcia; N C Fox; J Hardy; M C Deniz Naranjo; P Bosco; R Clarke; C Brayne; D Galimberti; M Mancuso; F Matthews; S Moebus; P Mecocci; M Del Zompo; W Maier; H Hampel; A Pilotto; M Bullido; F Panza; P Caffarra; B Nacmias; J R Gilbert; M Mayhaus; L Lannefelt; H Hakonarson; S Pichler; M M Carrasquillo; M Ingelsson; D Beekly; V Alvarez; F Zou; O Valladares; S G Younkin; E Coto; K L Hamilton-Nelson; W Gu; C Razquin; P Pastor; I Mateo; M J Owen; K M Faber; P V Jonsson; O Combarros; M C O'Donovan; L B Cantwell; H Soininen; D Blacker; S Mead; T H Mosley; D A Bennett; T B Harris; L Fratiglioni; C Holmes; R F de Bruijn; P Passmore; T J Montine; K Bettens; J I Rotter; A Brice; K Morgan; T M Foroud; W A Kukull; D Hannequin; J F Powell; M A Nalls; K Ritchie; K L Lunetta; J S Kauwe; E Boerwinkle; M Riemenschneider; M Boada; M Hiltuenen; E R Martin; R Schmidt; D Rujescu; L S Wang; J F Dartigues; R Mayeux; C Tzourio; A Hofman; M M Nöthen; C Graff; B M Psaty; L Jones; J L Haines; P A Holmans; M Lathrop; M A Pericak-Vance; L J Launer; L A Farrer; C M van Duijn; C Van Broeckhoven; V Moskvina; S Seshadri; J Williams; G D Schellenberg; P Amouyel Journal: Nat Genet Date: 2013-10-27 Impact factor: 38.330
Authors: Krista Fischer; Johannes Kettunen; Peter Würtz; Toomas Haller; Aki S Havulinna; Antti J Kangas; Pasi Soininen; Tõnu Esko; Mari-Liis Tammesoo; Reedik Mägi; Steven Smit; Aarno Palotie; Samuli Ripatti; Veikko Salomaa; Mika Ala-Korpela; Markus Perola; Andres Metspalu Journal: PLoS Med Date: 2014-02-25 Impact factor: 11.069
Authors: Alexandre Persu; Piotr Dobrowolski; Heather L Gornik; Jeffrey W Olin; David Adlam; Michel Azizi; Pierre Boutouyrie; Rosa Maria Bruno; Marion Boulanger; Jean-Baptiste Demoulin; Santhi K Ganesh; Tomasz J Guzik; Magdalena Januszewicz; Jason C Kovacic; Mariusz Kruk; Peter de Leeuw; Bart L Loeys; Marco Pappaccogli; Melanie H A M Perik; Emmanuel Touzé; Patricia Van der Niepen; Daan J L Van Twist; Ewa Warchoł-Celińska; Aleksander Prejbisz; Andrzej Januszewicz Journal: Cardiovasc Res Date: 2022-01-07 Impact factor: 10.787
Authors: Clint L Miller; Amy R Kontorovich; Ke Hao; Lijiang Ma; Conrad Iyegbe; Johan L M Björkegren; Jason C Kovacic Journal: J Am Coll Cardiol Date: 2021-05-25 Impact factor: 24.094
Authors: Adrien Georges; Min-Lee Yang; Takiy-Eddine Berrandou; Mark K Bakker; Ozan Dikilitas; Soto Romuald Kiando; Lijiang Ma; Benjamin A Satterfield; Sebanti Sengupta; Mengyao Yu; Jean-François Deleuze; Delia Dupré; Kristina L Hunker; Sergiy Kyryachenko; Lu Liu; Ines Sayoud-Sadeg; Laurence Amar; Chad M Brummett; Dawn M Coleman; Valentina d'Escamard; Peter de Leeuw; Natalia Fendrikova-Mahlay; Daniella Kadian-Dodov; Jun Z Li; Aurélien Lorthioir; Marco Pappaccogli; Aleksander Prejbisz; Witold Smigielski; James C Stanley; Matthew Zawistowski; Xiang Zhou; Sebastian Zöllner; Philippe Amouyel; Marc L De Buyzere; Stéphanie Debette; Piotr Dobrowolski; Wojciech Drygas; Heather L Gornik; Jeffrey W Olin; Jerzy Piwonski; Ernst R Rietzschel; Ynte M Ruigrok; Miikka Vikkula; Ewa Warchol Celinska; Andrzej Januszewicz; Iftikhar J Kullo; Michel Azizi; Xavier Jeunemaitre; Alexandre Persu; Jason C Kovacic; Santhi K Ganesh; Nabila Bouatia-Naji Journal: Nat Commun Date: 2021-10-15 Impact factor: 17.694
Authors: Siiri E Iismaa; Stephanie Hesselson; Lucy McGrath-Cadell; David W Muller; Diane Fatkin; Eleni Giannoulatou; Jason Kovacic; Robert M Graham Journal: Heart Lung Circ Date: 2020-07-06 Impact factor: 2.975
Authors: Adrien Georges; Juliette Albuisson; Takiy Berrandou; Délia Dupré; Aurélien Lorthioir; Valentina D'Escamard; Antonio F Di Narzo; Daniella Kadian-Dodov; Jeffrey W Olin; Ewa Warchol-Celinska; Aleksander Prejbisz; Andrzej Januszewicz; Patrick Bruneval; Anna A Baranowska; Tom R Webb; Stephen E Hamby; Nilesh J Samani; David Adlam; Natalia Fendrikova-Mahlay; Stanley Hazen; Yu Wang; Min-Lee Yang; Kristina Hunker; Nicolas Combaret; Pascal Motreff; Antoine Chédid; Béatrice Fiquet; Pierre-François Plouin; Elie Mousseaux; Arshid Azarine; Laurence Amar; Michel Azizi; Heather L Gornik; Santhi K Ganesh; Jason C Kovacic; Xavier Jeunemaitre; Nabila Bouatia-Naji Journal: Cardiovasc Res Date: 2021-03-21 Impact factor: 10.787