PWIII-002 - PHARMACOGENOMICS OF DILATED CARDIOMYOPATHY: POTENTIAL ROLE OF THE CDCP1 IN CARDIAC FIBROSIS.

M. Wang¹, D. Liu¹, V. Murthy¹, D. McNamara², T. Nguyen¹, T. Philips¹, M. Skime¹, A. Batzler¹, G. Jenkins¹, S. Pileggi³, L. Mestroni⁴, M. merlo⁵, F. Pinet⁶, R. Weinshilboum¹, N. Pereira¹; ¹Mayo Clinic, Rochester, MN, USA, ²University of Pittsburgh, Pittsburgh, PA, USA, ³Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, ⁴University of Colorado, Aurora, CO, USA, ⁵University of Trieste, Trieste, Italy, ⁶University Lille, Lille, France.

Background: Dilated Cardiomyopathy (DCM) remains a high mortality rate. Drug treatment response in DCM-related heart failure (HF) patients is highly variable, with some patients having little or no response. Pharmacogenomic study of DCM might identify biomarkers and provide insight into novel biology of DCM pharmacotherapy.

Methods: A genome-wide association study (GWAS) for DCM drug treatment response was performed in 686 Caucasian subjects with recent onset DCM. Changes in left ventricular ejection fraction (LVEF) in those DCM patients who received standard-of-care pharmacotherapy were used as the GWAS phenotype. GWAS signals were functionally validated in relevant cellular models to understand molecular mechanism(s) that contributed to DCM response to pharmacotherapy.

Results: The GWAS identified a single-nucleotide polymorphism (SNP) signal that mapped to the 5’-flanking region of the CUB domain containing protein 1 (CDCP1) gene (rs6773435, p=7.12E-07). The variant SNP allele was associated with improved cardiac function, and the SNP mapped to an annotated enhancer in human cardiac fibroblasts (HCFs). We demonstrated that the SNP variant allele was associated with decreased CDCP1 transcription, and that knock-down (KD) of CDCP1 represses HCF proliferation. Transcriptomic profiling after CDCP1 KD in HCFs suggested that CDCP1 regulates HCF proliferation through Ras/ERK signaling and mitosis. In addition, CDCP1 KD resulted in decreased expression of soluble ST2, a biomarker for heart failure, in HCFs. These results support the hypothesis that CDCP1 may negatively influence heart function recovery during DCM pharmacotherapy.

Conclusion: We identified the CDCP1 gene as a marker for DCM drug treatment response, potentially thought its role in cardiac fibroblasts proliferation and cardiac fibrosis.