Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure

• Type of Material: Article
• Authors: Brittany Butts, Emory University; Rebecca Gary, Emory University; Sandra Dunbar, Emory University; Javed Butler, Emory University
• Language: English
• Date: 2016-05-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cardfail.2015.12.004
• Title of Journal or Parent Work: Journal of Cardiac Failure
• ISSN: 1071-9164
• Volume: 22
• Issue: 5
• Start Page: 340
• End Page: 346
• Grant/Funding Information: Supported in part by PHS Grant UL1TR000454 from the Clinical and Translational Science Award Program, National Institutes of Health, National Center for Advancing Translational Sciences.; Effort for B. Butts was funded in part by the National Institutes of Health National Institute of Nursing Research grant numbers T32NR012715 (PI-S. Dunbar) and 1F31NR015180-01 (PI-B. Butts).
• Keywords: PROMOTER METHYLATION; Science & Technology; Cardiac & Cardiovascular Systems; Heart failure; ACUTE MYOCARDIAL-INFARCTION; ABERRANT METHYLATION; PROSTATE-CANCER; epigenetic; DNA METHYLATION; 6-MINUTE WALK TEST; Life Sciences & Biomedicine; BREAST-CANCER; inflammation; ASC GENE; NLRP3 INFLAMMASOME ACTIVATION; GENE PROMOTER; Cardiovascular System & Cardiology
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Background Heart failure (HF) is associated with inflammation characterized by the formation of the inflammasome, which triggers maturation of inflammatory cytokines. Apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), a vital component of the inflammasome, is controlled through epigenetic modification, which may be a candidate pathway for worsening HF. This study examined the inflammasome pathway in HF and the relationships between ASC CpG methylation and outcomes in HF. Methods and Results Stored samples from 155 HF outpatients (ejection fraction 29.9 ± 14.9%) were analyzed for percentage methylation of 7 CpG sites in the intron region preceding exon 1 of the ASC gene. ASC methylation was inversely related to ASC mRNA (r = -0.33; P <.001) and protein (r = -0.464; P <.001). ASC methylation had a positive linear relationship with ejection fraction (r = 0.85; P <.001), quality of life (r = 0.83; P <.001), and 6-minute walk test (r = 0.59; P =.023) and a negative linear relationship with depression (r = -0.81; P <.001) and anxiety (r = -0.75; P <.001). Higher ASC methylation was associated with a lower risk for clinical events (hazard ratio [HR] 0.16; P =.025), whereas higher protein (HR = 1.78; P =.045) and mRNA expression (HR = 1.18; P =.05) were associated with a greater risk. Conclusions Increased methylation of CpG sites in the intron region of ASC is associated with improved outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes and may represent a therapeutic target.