BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

1st Department of Internal Medicine Cardiology and Angiology St Anne's University Hospital and Masaryk University Brno Czech Republic

Cardiothoracovascular Department Azienda Sanitaria Universitaria Giuliano Isontina University of Trieste Italy

Cardiovascular Medicine Mayo Clinic Rochester MN

Cardiovascular Surgery Mayo Clinic Rochester MN

CHU Lille Service de Cardiologie France

Department of Cardiovascular Medicine Cleveland Clinic OH

Department of Cardiovascular Medicine Mayo Clinic Jacksonville FL

Department of Cardiovascular Research Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

Department of Medicine University of Pittsburgh PA

Departments of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester MN

Division of Cardiology Department of Medicine Cardiovascular Institute University of Colorado School of Medicine Aurora

Health Sciences Research Mayo Clinic Rochester MN

Medicine Mayo Clinic Rochester MN

Physiology and Biomedical Engineering Mayo Clinic Rochester MN

Pôle Cardio vasculaire et Pulmonaire University Lille Inserm CHU Lille Institut Pasteur de Lille France

Psychiatry and Psychology Mayo Clinic Rochester MN

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Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, et al. Heart Disease and Stroke Statistics—2014 Update: A Report From the American Heart Association. Circulation. 2014;129:e28–e292. doi: 10.1161/01.cir.0000441139.02102.80 PubMed DOI PMC

Rosenbaum AN, Agre KE, Pereira NL. Genetics of dilated cardiomyopathy: practical implications for heart failure management. Nat Rev Cardiol. 2020;17:286–297. doi: 10.1038/s41569-019-0284-0 PubMed DOI

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi: 10.1056/NEJMoa1409077 PubMed DOI

McNamara DM, Starling RC, Cooper LT, Boehmer JP, Mather PJ, Janosko KM, Gorcsan J 3rd, Kip KE, Dec GW, Investigators I. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Coll Cardiol. 2011;58:1112–1118. doi: 10.1016/j.jacc.2011.05.033 PubMed DOI PMC

Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol. 2010;56:392–406. doi: 10.1016/j.jacc.2010.05.011 PubMed DOI PMC

Sanseau P, Agarwal P, Barnes MR, Pastinen T, Richards JB, Cardon LR, Mooser V. Use of genome-wide association studies for drug repositioning. Nat Biotechnol. 2012;30:317–320. doi: 10.1038/nbt.2151 PubMed DOI

Meder B, Ruhle F, Weis T, Homuth G, Keller A, Franke J, Peil B, Lorenzo Bermejo J, Frese K, Huge A, et al. A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. Eur Heart J. 2014;35:1069–1077. doi: 10.1093/eurheartj/eht251 PubMed DOI

Noskovicova N, Heinzelmann K, Burgstaller G, Behr J, Eickelberg O. Cub domain-containing protein 1 negatively regulates TGF-beta signaling and myofibroblast differentiation. Am J Physiol Lung Cell Mol Physiol. 2018;314:L695–L707. doi: 10.1152/ajplung.00205.2017 PubMed DOI

Iwata M, Torok-Storb B, Wayner EA, Carter WG. CDCP1 identifies a CD146 negative subset of marrow fibroblasts involved with cytokine production. PLoS One. 2014;9:e109304. doi: 10.1371/journal.pone.0109304 PubMed DOI PMC

Schelbert EB, Piehler KM, Zareba KM, Moon JC, Ugander M, Messroghli DR, Valeti US, Chang CC, Shroff SG, Diez J, et al. Myocardial fibrosis quantified by extracellular volume is associated with subsequent hospitalization for heart failure, death, or both across the spectrum of ejection fraction and heart failure stage. J Am Heart Assoc. 2015;4. doi: 10.1161/jaha.115.002613 PubMed DOI PMC

Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7:827–840. doi: 10.1038/nrd2660 PubMed DOI PMC

Aimo A, Januzzi JL Jr., Bayes-Genis A, Vergaro G, Sciarrone P, Passino C, Emdin M. Clinical and Prognostic Significance of sST2 in Heart Failure: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;74:2193–2203. doi: 10.1016/j.jacc.2019.08.1039 PubMed DOI

Gupta M, Neavin D, Liu D, Biernacka J, Hall-Flavin D, Bobo WV, Frye MA, Skime M, Jenkins GD, Batzler A, et al. TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Mol Psychiatry. 2016;21:1717–1725. doi: 10.1038/mp.2016.6 PubMed DOI PMC

Liu D, Ray B, Neavin DR, Zhang J, Athreya AP, Biernacka JM, Bobo WV, Hall-Flavin DK, Skime MK, Zhu H, et al. Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Transl Psychiatry. 2018;8:10. doi: 10.1038/s41398-017-0056-8 PubMed DOI PMC

Fasching PA, Liu D, Scully S, Ingle JN, Lyra PC, Rack B, Hein A, Ekici AB, Reis A, Schneeweiss A, et al. Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer. Clin Cancer Res. 2022;28:3342–3355. doi: 10.1158/1078-0432.CCR-20-4774 PubMed DOI PMC

Liu D, Zhuang Y, Zhang L, Gao H, Neavin D, Carrillo-Roa T, Wang Y, Yu J, Qin S, Kim DC, et al. ERICH3: vesicular association and antidepressant treatment response. Mol Psychiatry. 2021;26:2415–2428. doi: 10.1038/s41380-020-00940-y PubMed DOI PMC

de Groote P, Helbecque N, Lamblin N, Hermant X, Amouyel P, Bauters C, Dallongeville J. Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion polymorphism in patients with chronic heart failure. Eur J Heart Fail. 2004;6:17–21. doi: 10.1016/j.ejheart.2003.09.006 PubMed DOI

Lemesle G, Maury F, Beseme O, Ovart L, Amouyel P, Lamblin N, de Groote P, Bauters C, Pinet F. Multimarker proteomic profiling for the prediction of cardiovascular mortality in patients with chronic heart failure. PLoS One. 2015;10:e0119265. doi: 10.1371/journal.pone.0119265 PubMed DOI PMC

TheGoTExConsortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–585. doi: 10.1038/ng.2653 PubMed DOI PMC

EncodeProjectConsortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74. doi: 10.1038/nature11247 PubMed DOI PMC

Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–26. doi: 10.1038/nbt.1754 PubMed DOI PMC

Schneider BP, Shen F, Gardner L, Radovich M, Li L, Miller KD, Jiang G, Lai D, O’Neill A, Sparano JA, et al. Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure. Clin Cancer Res. 2017;23:43–51. doi: 10.1158/1078-0432.CCR-16-0908 PubMed DOI PMC

Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Cupples LA, Dehghan A, Lumley T, Rosamond WD, et al. Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Circ Cardiovasc Genet. 2010;3:256–266. doi: 10.1161/CIRCGENETICS.109.895763 PubMed DOI PMC

Li W, Notani D, Rosenfeld MG. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet. 2016;17:207–223. doi: 10.1038/nrg.2016.4 PubMed DOI

Khan T, Kryza T, Lyons NJ, He Y, Hooper JD. The CDCP1 Signaling Hub: A Target for Cancer Detection and Therapeutic Intervention. Cancer Res. 2021;81:2259–2269. doi: 10.1158/0008-5472.CAN-20-2978 PubMed DOI

Alajati A, D’Ambrosio M, Troiani M, Mosole S, Pellegrini L, Chen J, Revandkar A, Bolis M, Theurillat JP, Guccini I, et al. CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo. J Clin Invest. 2020;130:2435–2450. doi: 10.1172/JCI131133 PubMed DOI PMC

Forte L, Turdo F, Ghirelli C, Aiello P, Casalini P, Iorio MV, D’Ippolito E, Gasparini P, Agresti R, Belmonte B, et al. The PDGFRbeta/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer. BMC Cancer. 2018;18:586. doi: 10.1186/s12885-018-4500-9 PubMed DOI PMC

Karachaliou N, Chaib I, Cardona AF, Berenguer J, Bracht JWP, Yang J, Cai X, Wang Z, Hu C, Drozdowskyj A, et al. Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis. EBioMedicine. 2018;29:112–127. doi: 10.1016/j.ebiom.2018.02.001 PubMed DOI PMC

Liu H, Ong SE, Badu-Nkansah K, Schindler J, White FM, Hynes RO. CUB-domain-containing protein 1 (CDCP1) activates Src to promote melanoma metastasis. Proc Natl Acad Sci U S A. 2011;108:1379–1384. doi: 10.1073/pnas.1017228108 PubMed DOI PMC

Lim SA, Zhou J, Martinko AJ, Wang YH, Filippova EV, Steri V, Wang D, Remesh SG, Liu J, Hann B, et al. Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers. J Clin Invest. 2022;132. doi: 10.1172/JCI154604 PubMed DOI PMC

Ahlers MJ, Lowery BD, Farber-Eger E, Wang TJ, Bradham W, Ormseth MJ, Chung CP, Stein CM, Gupta DK. Heart Failure Risk Associated With Rheumatoid Arthritis-Related Chronic Inflammation. J Am Heart Assoc. 2020;9:e014661. doi: 10.1161/JAHA.119.014661 PubMed DOI PMC

Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, Wilson KM, Onel K, Geanon D, Tuballes K, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. 2020;183:982–995 e914. doi: 10.1016/j.cell.2020.09.034 PubMed DOI PMC

Lun Y, Borjini N, Miura NN, Ohno N, Singer NG, Lin F. CDCP1 on Dendritic Cells Contributes to the Development of a Model of Kawasaki Disease. J Immunol. 2021. doi: 10.4049/jimmunol.2001406 PubMed DOI PMC

Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: The fibroblast awakens. Circ Res. 2016;118:1021–1040. doi: 10.1161/CIRCRESAHA.115.306565 PubMed DOI PMC

Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021;117:1450–1488. doi: 10.1093/cvr/cvaa324 PubMed DOI PMC

Schreibing F, Anslinger TM, Kramann R. Fibrosis in Pathology of Heart and Kidney: From Deep RNA-Sequencing to Novel Molecular Targets. Circ Res. 2023;132:1013–1033. doi: 10.1161/CIRCRESAHA.122.321761 PubMed DOI

Gallini R, Lindblom P, Bondjers C, Betsholtz C, Andrae J. PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice. Exp Cell Res. 2016;349:282–290. doi: 10.1016/j.yexcr.2016.10.022 PubMed DOI

Manning BD, Toker A. AKT/PKB Signaling: Navigating the Network. Cell. 2017;169:381–405. doi: 10.1016/j.cell.2017.04.001 PubMed DOI PMC

McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263–1284. doi: 10.1016/j.bbamcr.2006.10.001 PubMed DOI PMC

Kimura SH, Ikawa M, Ito A, Okabe M, Nojima H. Cyclin G1 is involved in G2/M arrest in response to DNA damage and in growth control after damage recovery. Oncogene. 2001;20:3290–3300. doi: 10.1038/sj.onc.1204270 PubMed DOI

Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, Brody MJ, SC JL, Aronow BJ, Tallquist MD, et al. Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun. 2016;7:12260. doi: 10.1038/ncomms12260 PubMed DOI PMC

Moore-Morris T, Guimaraes-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest. 2014;124:2921–2934. doi: 10.1172/JCI74783 PubMed DOI PMC

González A, Schelbert EB, Díez J, Butler J. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol. 2018;71:1696–1706. doi: 10.1016/j.jacc.2018.02.021 PubMed DOI

Dai Z, Aoki T, Fukumoto Y, Shimokawa H. Coronary perivascular fibrosis is associated with impairment of coronary blood flow in patients with non-ischemic heart failure. J Cardiol. 2012;60:416–421. doi: 10.1016/j.jjcc.2012.06.009 PubMed DOI

Villari B, Campbell SE, Hess OM, Mall G, Vassalli G, Weber KT, Krayenbuehl HP. Influence of collagen network on left ventricular systolic and diastolic function in aortic valve disease. J Am Coll Cardiol. 1993;22:1477–1484. doi: 10.1016/0735-1097(93)90560-n PubMed DOI

Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, Morarji K, Brown TD, Ismail NA, Dweck MR, et al. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA. 2013;309:896–908. doi: 10.1001/jama.2013.1363 PubMed DOI

Azevedo CF, Nigri M, Higuchi ML, Pomerantzeff PM, Spina GS, Sampaio RO, Tarasoutchi F, Grinberg M, Rochitte CE. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol. 2010;56:278–287. doi: 10.1016/j.jacc.2009.12.074 PubMed DOI

Yamada T, Fukunami M, Ohmori M, Iwakura K, Kumagai K, Kondoh N, Minamino T, Tsujimura E, Nagareda T, Kotoh K, et al. Which subgroup of patients with dilated cardiomyopathy would benefit from long-term beta-blocker therapy? A histologic viewpoint. J Am Coll Cardiol. 1993;21:628–633. doi: 10.1016/0735-1097(93)90094-h PubMed DOI

Masci PG, Schuurman R, Andrea B, Ripoli A, Coceani M, Chiappino S, Todiere G, Srebot V, Passino C, Aquaro GD, et al. Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study. Circ Cardiovasc Imaging. 2013;6:790–799. doi: 10.1161/circimaging.113.000438 PubMed DOI

De Mello WC, Specht P. Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication, reduced fibrosis and improved impulse propagation in the failing heart. J Renin Angiotensin Aldosterone Syst. 2006;7:201–205. doi: 10.3317/jraas.2006.038 PubMed DOI

Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000;102:2700–2706. doi: 10.1161/01.cir.102.22.2700 PubMed DOI

Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, Scholler J, Monslow J, Lo A, Han W, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430–433. doi: 10.1038/s41586-019-1546-z PubMed DOI PMC

Ivey MJ, Kuwabara JT, Riggsbee KL, Tallquist MD. Platelet-derived growth factor receptor-alpha is essential for cardiac fibroblast survival. Am J Physiol Heart Circ Physiol. 2019;317:H330–H344. doi: 10.1152/ajpheart.00054.2019 PubMed DOI PMC

Kuwabara JT, Hara A, Bhutada S, Gojanovich GS, Chen J, Hokutan K, Shettigar V, Lee AY, DeAngelo LP, Heckl JR, et al. Consequences of PDGFRalpha(+) fibroblast reduction in adult murine hearts. Elife. 2022;11. doi: 10.7554/eLife.69854 PubMed DOI PMC

Nguyen TTL, Gao H, Liu D, Philips TJ, Ye Z, Lee JH, Shi GX, Copenhaver K, Zhang L, Wei L, et al. Glucocorticoids unmask silent non-coding genetic risk variants for common diseases. Nucleic Acids Res. 2022;50:11635–11653. doi: 10.1093/nar/gkac1045 PubMed DOI PMC

Liu D, Nguyen TTL, Gao H, Huang H, Kim DC, Sharp B, Ye Z, Lee JH, Coombes BJ, Ordog T, et al. TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling. Mol Psychiatry. 2021;26:7454–7464. doi: 10.1038/s41380-021-01274-z PubMed DOI PMC

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, Kang HM, Fuchsberger C, Danecek P, Sharp K, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48:1279–1283. doi: 10.1038/ng.3643 PubMed DOI PMC

Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, Vrieze SI, Chew EY, Levy S, McGue M, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–1287. doi: 10.1038/ng.3656 PubMed DOI PMC

Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, et al. A global reference for human genetic variation. Nature. 2015;526:68–74. doi: 10.1038/nature15393 PubMed DOI PMC