Correlation of Peripheral Blood Gene Expression with the Extent of Coronary Artery Stenosis
Journal: Circulation: Cardiovascular Genetics. 1(1):31-38, October 2008
Authors: James A. Wingrove, PhD, Susan E. Daniels, PhD, Amy J. Sehnert, MD, Whittemore Tingley, MD, PhD, Michael R. Elashoff, PhD and Steven Rosenberg, PhD, CardioDx, Palo Alto, CA and Lutz Buellesfeld MD, and Eberhard Grube, MD, Helios Heart Center, Siegburg, Germany, L. Kristin Newby, MD, MHS, Geoffrey S. Ginsburg, MD, PhD and William E. Kraus, MD, Division of Cardiovascular Medicine, Duke University, Durham, NC.
Abstract:
Background
The molecular pathophysiology of coronary artery disease (CAD) includes cytokine release and a localized inflammatory response within the vessel wall. The extent to which CAD and its severity is reflected by gene expression in circulating cells is unknown.
Methods and Results
From an initial coronary catheterization cohort we identified 41 subjects, comprising 27 cases with angiographically significant CAD and 14 controls without coronary stenosis. Whole genome microarray analysis performed on peripheral blood mononuclear cells (PBMC) yielded 526 genes with >1.3-fold differential expression (p <0.05) between cases and controls. Real-time polymerase chain reaction (RT-PCR) on 106 genes, (the 50 most significant microarray genes, and 56 additional literature genes) in an independent subset of 95 subjects (63 cases, 32 controls) from the same cohort yielded 14 genes p <0.05 that independently discriminated CAD state in multivariable analysis including clinical and demographic factors. From an independent second catheterization cohort, 215 patients were selected for RT-PCR-based replication. A case:control subset of 107 patients (86 cases, 21 controls) replicated 11 of the 14 multivariably significant genes from the first cohort. An analysis of the 14 genes in the entire set of 215 patients demonstrated that gene expression was proportional to maximal coronary artery stenosis (p<0.001 by ANOVA).
Conclusions
Gene expression in peripheral blood cells reflects the presence and extent of CAD in patients undergoing angiography.
Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated With Carvedilol or Metoprolol
Journal: Journal of the American College of Cardiology: JACC. 2008; 52:644-651
Authors: Amy J. Sehnert, MD, Susan E. Daniels, PhD, Michael Elashoff, PhD, James A. Wingrove, PhD, Christopher R. Burrow, MD, Benjamin Horne, PhD, Joseph B. Muhlestein, MD, FACC, Mark Donahue, MD, Stephen B. Liggett, MD, Jeffrey L. Anderson, MD, FACC, William E. Kraus, MD, FACC
Abstract:
Objectives
To investigate the role of adrenergic receptor genetics on transplant-free survival in heart failure (HF).
Background
Discordant results exist for genetic associations between adrenergic receptor alleles and endpoints of beta-blocker response in HF patients.
Methods
We identified 637 patients enrolled in two US cardiovascular genetic registries with HF and left ventricular systolic dysfunction who were discharged on beta-blocker, angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), and diuretic. Endpoints were determined through the national Social Security death index and transplant records. We genotyped five polymorphisms in three genes: ADRB1 (S49G, R389G), ADRB2 (G16R, Q27E), and ADRA2C (Del322-325) using 5’ nuclease assays and performed a multivariable clinical:genetic analysis.
Results
A total of 190 events (29.8%) occurred over a median follow-up of 1070 days. Multivariable analysis revealed a significant effect of four clinical factors on survival: age (p=0.006), gender (p=0.005), ejection fraction (EF) (p=0.0002), and hemoglobin (p=0.00010). There was no significant effect of the polymorphisms or haplotypes analyzed on survival.
Conclusions
Genotypes and haplotypes of ADRB1, ADRB2, and ADRA2C did not significantly affect survival in metoprolol or carvediolol treated HF patients in this study. These results complement the findings of two similarly designed previous studies, but do not replicate an association of ADRB2 haplotypes and survival. All three studies differ from a survival benefit reported for bucindolol treated homozygous ADRB1 R389 individuals. This may be due to a drug-specific interaction between genotype and outcome with bucindolol, which does not appear to occur with metoprolol or carvediolol.
