TY - JOUR
T1 - Druggable proteins influencing cardiac structure and function
T2 - Implications for heart failure therapies and cancer cardiotoxicity
AU - Schmidt, Amand F.
AU - Bourfiss, Mimount
AU - Alasiri, Abdulrahman
AU - Puyol-Anton, Esther
AU - Chopade, Sandesh
AU - van Vugt, Marion
AU - van der Laan, Sander W.
AU - Gross, Christian
AU - Clarkson, Chris
AU - Henry, Albert
AU - Lumbers, Tom R.
AU - van der Harst, Pim
AU - Franceschini, Nora
AU - Bis, Joshua C.
AU - Velthuis, Birgitta K.
AU - te Riele, Anneline S. J. M.
AU - Hingorani, Aroon D.
AU - Ruijsink, Bram
AU - Asselbergs, Folkert W.
AU - van Setten, Jessica
AU - Finan, Chris
PY - 2023/4/28
Y1 - 2023/4/28
N2 - Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.
AB - Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.
KW - Atrial Fibrillation
KW - Cardiomyopathy, Dilated
KW - Cardiotoxicity
KW - Genome-Wide Association Study
KW - Glypicans
KW - Heart Failure
KW - Humans
KW - Neoplasms
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85158033415&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/37126556
UR - http://www.scopus.com/inward/record.url?scp=85158033415&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciadv.add4984
DO - https://doi.org/10.1126/sciadv.add4984
M3 - Article
C2 - 37126556
SN - 2375-2548
VL - 9
SP - eadd4984
JO - Science Advances
JF - Science Advances
IS - 17
ER -