Abstracts from the Emerging Science Series, June 19, 2013
CPT1A Methylation is a Novel Epigenetic Marker of Cardiovascular Risk
Stella Aslibekyan, Marguerite M. Irvin, Jin Sha, Degui Zhi, Univ of Alabama at Birmingham, Birmingham, AL; Krista Stanton Thibeault, Hudson Alpha Inst for Biotechnology, Huntsville, AL; Michael Y. Tsai, Univ of Minnesota, Minneapolis, MN; Paul Hopkins, Univ of Utah, Salt Lake City, UT; Ingrid B. Borecki, Washington Univ at St Louis, St Louis, MO; Jose M. Ordovas, Tufts Univ, Boston, MA; Devin M. Absher, Hudson Alpha Inst for Biotechnology, Huntsville, AL; Donna K. Arnett, Univ of Alabama at Birmingham, Birmingham, AL
Introduction: Inter-individual variability in plasma lipid levels and other cardiovascular risk phenotypes is influenced by both genetic and environmental factors. However, known predictors explain only a limited portion of the observed variability. We hypothesized that epigenetic changes such as DNA methylation contribute to the architecture of complex metabolic traits such as plasma lipids and thus affect cardiovascular risk. Methods: We isolated DNA from CD4+ T-cells and quantified methylation at 461,281 CpG sites using the Infinium HumanMethylation450 BeadChip Kit in 888 participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Participants were randomly allocated to either discovery (n=593) or replication (n=295) data subsets. In the discovery stage, we modeled percent methylation at each CpG site as a function of fasting plasma lipids and adiponectin using mixed linear regression models adjusted for age, gender, study site, cell purity, and family structure. After applying a Bonferroni correction for multiple testing, we evaluated all markers that reached statistical significance for association with the trait of interest in the replication data set. Results: In the discovery stage, methylation at two intronic CpG sites (cg00574958 and cg17058475) of the gene encoding carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in lipid metabolism, was strongly associated with triglyceride levels (P= 5.3x10-14 and 1.2x10-9 respectively) and very low-density lipoprotein (VLDL) cholesterol levels (P<1.0x10-8). Additionally, we found robust associations between methylation in cg00574958 in CPT1A and plasma adiponectin (P<1.0x10-9). We successfully replicated the associations with triglycerides and adiponectin (P<1.0x10-6). Conclusions: We have identified differential DNA methylation in CPT1A as a novel contributor to inter-individual variability in plasma triglycerides, VLDL cholesterol, and adiponectin. Our findings lay the groundwork for incorporating epigenetic data in cardiovascular risk stratification, disease prevention, and treatment strategies.
S. Aslibekyan: None. M.M.D. Irvin: None. J. Sha: None. D. Zhi: None. K. Stanton Thibeault: None. M.Y. Tsai: None. P. Hopkins: None. I.B. Borecki: None. J.M. Ordovas: None. D.M. Absher: None. D.K. Arnett: None.
The Incidence of Kidney Injury for Patients Treated with Intensive versus Less Potent Statin Therapy after an Acute Coronary Syndrome
Amy Sarma, Christopher P Cannon, Stephen D Wiviott, Marc S Sabatine, Marc A Pfeffer, Elaine B Hoffman, Jianping Guo, Brigham and Women’s Hosp, Boston, MA; James A de Lemos, UT Southwestern, Dallas, TX; Michelle L O’Donoghue, Brigham and Women’s Hosp, Boston, MA
Background: Statins are widely used to reduce the risk of cardiovascular (CV) events in primary and secondary prevention. Concerns have been raised that high potency statins increase the risk of acute kidney injury when compared to lower potency statins. Since analyses from observational datasets are subject to residual confounding, we examined the incidence of kidney injury in two randomized trials of intensive versus moderate statin therapy in patients after an acute coronary syndrome (ACS). Methods: The PROVE IT-TIMI 22 trial was a randomized double-blind trial of 4162 patients to evaluate intensive (atorvastatin 80 mg daily) versus moderate (pravastatin 40 mg daily) statin therapy for the prevention of MACE following ACS. The Phase Z portion of the A-to-Z trial was a randomized double-blind trial of 4497 patients with ACS to compare the early initiation of intensive statin (simvastatin 40mg/d x1 month, then simvastatin 80mg/d thereafter) versus delayed initiation of a less intensive regimen (placebo for 4 months, then simvastatin 20mg/d). In both trials, serum creatinine was to be assessed at baseline and serial timepoints during follow-up. The incidence of kidney injury was adapted according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification with baseline creatinine as the referent. The incidence of adverse events (AEs) relating to kidney injury was determined through review of the AE database. Results: In PROVE IT-TIMI 22, the baseline mean serum creatinine was 1.03(±0.24) mg/dl; in A-to-Z, the baseline mean serum creatinine was 1.14(±0.26) mg/dl. Across both trials, the relative change in serum creatinine over time was the same between treatment arms. The incidence of kidney injury identified through creatinine elevation was similar between treatment arms in both trials (Figure). When data were combined across trials, the incidence of AEs related to kidney injury was similar for patients on intensive versus less potent statin therapy (0.92% versus 0.91%, P=0.97, respectively). Conclusions: Across two large randomized trials of patients after an ACS, the use of intensive statin therapy did not increase the risk of kidney injury when compared to a less potent statin regimen.
A. Sarma: None. C.P. Cannon: Research Grant; Modest; Accumetrics, Essentialis, Regeneron, Sanofi aventis. Research Grant; Significant; GSK, AstraZeneca, Merck, Takeda. Consultant/Advisory Board; Modest; Alnylam, BMS, CSL Behring, Lipimedix, Pfizer. S.D. Wiviott: Research Grant; Significant; AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, BMS. Consultant/Advisory Board; Modest; Aegerion, Angelmed, ICON, Eisai, J&J, Jannsen, Xoma. M.S. Sabatine: Research Grant; Significant; Amgen, AstraZeneca, AstraZeneca/BMS Alliance, BMS/sanofi aventis joint venture, Daiichi Sankyo, Eisai, Genzyme, GSK, Intarcia, Merck, sanofi aventis, Takeda, Abbott, Accumetrics, Critical Diagnostics, Nanosphere, Roche. Consultant/Advisory Board; Modest; Aegerion, Amgen, AZ/BMS Alliance, Diasorin, GSK, Merck, Pfizer, sanofi aventis, Vertex. M.A. Pfeffer: Research Grant; Significant; Amgen, Cellandon, Novartis, Sanofi Aventis. Consultant/Advisory Board; Modest; Aastrom, Amgen, BMS, Cerenis, Concert, Genzyme, Keryx, Medtronic, Merck, Novartis, Roche, Servier, Teva, Xoma. E.B. Hoffman: None. J. Guo: None. J.A. de Lemos: Honoraria; Modest; AstraZeneca. Consultant/Advisory Board; Modest; Janssen. M.L. O’Donoghue: Research Grant; Modest; AstraZeneca, Genzyme. Research Grant; Significant; GlaxoSmithKline. Consultant/Advisory Board; Modest; Aegerion.
- © 2013 American Heart Association, Inc.