Jasmine A Luzum1,2, Christopher Ting3, Edward L Peterson4, Hongsheng Gui5, Tyler Shugg6, L Keoki Williams5, Liang Li7, Wolfgang Sadee8, Danxin Wang9, David E Lanfear5,10. 1. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA. jluzum@umich.edu. 2. Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, MI, USA. jluzum@umich.edu. 3. Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA. 4. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA. 5. Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, MI, USA. 6. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA. 7. Department of Medical Genetics, Southern Medical University, Guangzhou, China. 8. Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of Medicine, Ohio State University, Columbus, OH, USA. 9. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA. 10. Heart and Vascular Institute, Henry Ford Health System, Detroit, MI, USA.
Abstract
PURPOSE: Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown. METHODS: Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n = 951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models. RESULTS: The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR = 0.81 (95% CI = 0.67-0.98), p = 0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p > 0.1 for all). CONCLUSIONS: A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.
PURPOSE:Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown. METHODS:Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n = 951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models. RESULTS: The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR = 0.81 (95% CI = 0.67-0.98), p = 0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p > 0.1 for all). CONCLUSIONS: A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.
Entities:
Keywords:
Heart failure; Mortality; Protein kinase Cα (PRKCA); Regulatory variants
Authors: Fen-Lai Tan; Christine S Moravec; Jianbo Li; Carolyn Apperson-Hansen; Patrick M McCarthy; James B Young; Meredith Bond Journal: Proc Natl Acad Sci U S A Date: 2002-08-12 Impact factor: 11.205
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Sayantan Das; Lukas Forer; Sebastian Schönherr; Carlo Sidore; Adam E Locke; Alan Kwong; Scott I Vrieze; Emily Y Chew; Shawn Levy; Matt McGue; David Schlessinger; Dwight Stambolian; Po-Ru Loh; William G Iacono; Anand Swaroop; Laura J Scott; Francesco Cucca; Florian Kronenberg; Michael Boehnke; Gonçalo R Abecasis; Christian Fuchsberger Journal: Nat Genet Date: 2016-08-29 Impact factor: 38.330
Authors: N Bowling; R A Walsh; G Song; T Estridge; G E Sandusky; R L Fouts; K Mintze; T Pickard; R Roden; M R Bristow; H N Sabbah; J L Mizrahi; G Gromo; G L King; C J Vlahos Journal: Circulation Date: 1999-01-26 Impact factor: 29.690
Authors: Qinghang Liu; Xiongwen Chen; Scott M Macdonnell; Evangelia G Kranias; John N Lorenz; Michael Leitges; Steven R Houser; Jeffery D Molkentin Journal: Circ Res Date: 2009-06-25 Impact factor: 17.367
Authors: Goncalo R Abecasis; Adam Auton; Lisa D Brooks; Mark A DePristo; Richard M Durbin; Robert E Handsaker; Hyun Min Kang; Gabor T Marth; Gil A McVean Journal: Nature Date: 2012-11-01 Impact factor: 49.962