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ABSTRACT: Myocardin is a muscle lineage-restricted transcriptional coactivator that has been shown to transduce extracellular signals to the nucleus required for SMC differentiation. We now report the discovery of a myocardin/BMP10 (where BMP10 indicates bone morphogenetic protein 10) signaling pathway required for cardiac growth, chamber maturation, and embryonic survival. Myocardin-null (Myocd) embryos and embryos harboring a cardiomyocyte-restricted mutation in the Myocd gene exhibited myocardial hypoplasia, defective atrial and ventricular chamber maturation, heart failure, and embryonic lethality. Cardiac hypoplasia was caused by decreased cardiomyocyte proliferation accompanied by a dramatic increase in programmed cell death. Defective chamber maturation and the block in cardiomyocyte proliferation were caused in part by a block in BMP10 signaling. Myocardin transactivated the Bmp10 gene via binding of a serum response factor-myocardin protein complex to a nonconsensus CArG element in the Bmp10 promoter. Expression of p57kip2, a BMP10-regulated cyclin-dependent kinase inhibitor, was induced in Myocd-/- hearts, while BMP10-activated cardiogenic transcription factors, including NKX2.5 and MEF2c, were repressed. Remarkably, when embryonic Myocd-/- hearts were cultured ex vivo in BMP10-conditioned medium, the defects in cardiomyocyte proliferation and p57kip2 expression were rescued. Taken together, these data identify a heretofore undescribed myocardin/BMP10 signaling pathway that regulates cardiomyocyte proliferation and apoptosis in the embryonic heart.
The Journal of clinical investigation 09/2012; 122(10):3678-91. · 15.39 Impact Factor
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ABSTRACT: The molecular mechanisms that regulate and coordinate signaling between the extracellular matrix (ECM) and cells contributing to the developing vasculature are complex and poorly understood. Myocardin-like protein 2 (MKL2) is a transcriptional co-activator that in response to RhoA and cytoskeletal actin signals physically associates with serum response factor (SRF), activating a subset of SRF-regulated genes. We now report the discovery of a previously undescribed MKL2/TGFβ signaling pathway in embryonic stem (ES) cells that is required for maturation and stabilization of the embryonic vasculature. Mkl2(-/-) null embryos exhibit profound derangements in the tunica media of select arteries and arterial beds, which leads to aneurysmal dilation, dissection and hemorrhage. Remarkably, TGFβ expression, TGFβ signaling and TGFβ-regulated genes encoding ECM are downregulated in Mkl2(-/-) ES cells and the vasculature of Mkl2(-/-) embryos. The gene encoding TGFβ2, the predominant TGFβ isoform expressed in vascular smooth muscle cells and embryonic vasculature, is activated directly via binding of an MKL2/SRF protein complex to a conserved CArG box in the TGFβ2 promoter. Moreover, Mkl2(-/-) ES cells exhibit derangements in cytoskeletal organization, cell adhesion and expression of ECM that are rescued by forced expression of TGFβ2. Taken together, these data demonstrate that MKL2 regulates a conserved TGF-β signaling pathway that is required for angiogenesis and ultimately embryonic survival.
Development 08/2012; 139(19):3531-42. · 6.60 Impact Factor
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ABSTRACT: Heart failure research suggests that multiple biomarkers could be combined with relevant clinical information to more accurately quantify individual risk and guide patient-specific treatment strategies. Therefore, statistical methodology is required to determine multi-marker risk scores that yield improved prognostic performance. Development of a prognostic score that combines biomarkers with clinical variables requires specification of an appropriate statistical model and is most frequently achieved using standard regression methods such as Cox regression. We demonstrate that care is needed in model specification and that maximal use of marker information requires consideration of potential non-linear effects and interactions. The derived multi-marker score can be evaluated using time-dependent receiver operating characteristic methods, or risk reclassification methods adapted for survival outcomes. We compare the performance of alternative model accuracy methods using simulations, both to evaluate power and to quantify the potential loss in accuracy associated with use of a sub-optimal regression model to develop the multi-marker score. We illustrate development and evaluation strategies using data from the Penn Heart Failure Study. Based on our results, we recommend that analysts carefully examine the functional form for component markers and consider plausible forms for effect modification to maximize the prognostic potential of a model-derived multi-marker score.
Statistical Methods in Medical Research 07/2012; · 2.44 Impact Factor
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ABSTRACT: Prior studies have suggested using a panel of biomarkers that measure diverse biological processes as a prognostic tool in chronic heart failure. Whether this approach improves risk prediction beyond clinical evaluation is unknown.
In a multicenter cohort of 1513 chronic systolic heart failure patients, we measured a contemporary biomarker panel consisting of high-sensitivity C-reactive protein, myeloperoxidase, B-type natriuretic peptide, soluble fms-like tyrosine kinase receptor-1, troponin I, soluble toll-like receptor-2, creatinine, and uric acid. From this panel, we calculated a parsimonious multimarker score and assessed its performance in predicting risk of death, cardiac transplantation, or ventricular assist device placement in comparison to an established clinical risk score, the Seattle Heart Failure Model (SHFM). During a median follow-up of 2.5 years, there were 317 outcomes: 187 patients died; 99 were transplanted; and 31 had a ventricular assist device placed. In unadjusted Cox models, patients in the highest tertile of the multimarker score had a 13.7-fold increased risk of adverse outcomes compared with the lowest tertile (95% confidence interval, 8.75-21.5). These effects were independent of the SHFM (adjusted hazard ratio, 6.80; 95% confidence interval, 4.18-11.1). Addition of the multimarker score to the SHFM led to a significantly improved area under the receiver operating characteristic curve of 0.803 versus 0.756 (P=0.003) and appropriately reclassified a significant number of patients who had the outcome into a higher risk category (net reclassification improvement, 25.2%; 95% confidence interval, 14.2-36.2%; P<0.001).
In ambulatory chronic heart failure patients, a score derived from multiple biomarkers integrating diverse biological pathways substantially improves prediction of adverse events beyond current metrics.
Circulation Heart Failure 02/2012; 5(2):183-90. · 6.29 Impact Factor
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Richa Saxena,
Clara C Elbers,
Yiran Guo,
Inga Peter,
Tom R Gaunt,
Jessica L Mega,
Matthew B Lanktree,
Archana Tare,
Berta Almoguera Castillo,
Yun R Li, [......],
Paul I W de Bakker,
Jeanne McCaffery,
Cisca Wijmenga,
Marc S Sabatine,
James G Wilson,
Alex Reiner,
Donald W Bowden,
Hakon Hakonarson,
David S Siscovick,
Brendan J Keating
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ABSTRACT: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
The American Journal of Human Genetics 02/2012; 90(3):410-25. · 10.60 Impact Factor
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ABSTRACT: The general availability of reliable and affordable genotyping technology has enabled genetic association studies to move beyond small case-control studies to large prospective studies. For prospective studies, genetic information can be integrated into the analysis via haplotypes, with focus on their association with a censored survival outcome. We develop non-iterative, regression-based methods to estimate associations between common haplotypes and a censored survival outcome in large cohort studies. Our non-iterative methods--weighted estimation and weighted haplotype combination--are both based on the Cox regression model, but differ in how the imputed haplotypes are integrated into the model. Our approaches enable haplotype imputation to be performed once as a simple data-processing step, and thus avoid implementation based on sophisticated algorithms that iterate between haplotype imputation and risk estimation. We show that non-iterative weighted estimation and weighted haplotype combination provide valid tests for genetic associations and reliable estimates of moderate associations between common haplotypes and a censored survival outcome, and are straightforward to implement in standard statistical software. We apply the methods to an analysis of HSPB7-CLCNKA haplotypes and risk of adverse outcomes in a prospective cohort study of outpatients with chronic heart failure.
Statistical Applications in Genetics and Molecular Biology 01/2012; 11(3):Article 4. · 1.52 Impact Factor
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Circulation Cardiovascular Genetics 12/2011; 4(6):701-9. · 6.11 Impact Factor
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ABSTRACT: Recognizing that inhibitors of phosphodiesterase type 5 (PDE5) are increasingly employed in patients with pulmonary hypertension and right ventricular (RV) failure, we examined PDE5 expression in the human RV and its impact on myocardial contractility.
Tissue extracts from the RV of 20 patients were assayed for PDE5 expression using immunoblot and immunohistochemical staining. Tissues were selected from groups of nonfailing organ donors and transplant recipients with endstage ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. Among dilated cardiomyopathy patients, subgroups with mild or severe RV dysfunction and prior left ventricular assist devices were analyzed separately. Our results showed that PDE5 abundance increased more than 4-fold in the RVs of the ischemic cardiomyopathy compared with the nonfailing group. In dilated cardiomyopathy, PDE5 upregulation was more moderate and varied with the severity of RV dysfunction. Immunohistochemical staining confirmed that cardiac myocytes contributed to the upregulation in the failing hearts. In functional studies, PDE5 inhibition produced little change in developed force in RV trabeculae from nonfailing hearts but produced a moderate increase in RV trabeculae from failing hearts.
Our results showed the etiology- and severity-dependent upregulation of myocyte PDE5 expression in the RV and the impact of this upregulation on myocardial contractility. These findings suggest that RV PDE5 expression could contribute to the pathogenesis of RV failure, and direct myocardial responses to PDE5 inhibition may modulate the indirect responses mediated by RV afterload reduction.
Circulation Heart Failure 12/2011; 5(1):79-86. · 6.29 Impact Factor
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ABSTRACT: In the setting of acute decompensated heart failure, worsening renal function (WRF) and improved renal function (IRF) have been associated with similar hemodynamic derangements and poor prognosis. Our aim was to further characterize IRF and its associated mortality risk.
Consecutive patients with a discharge diagnosis of congestive heart failure at the Hospital of the University of Pennsylvania were reviewed. IRF was defined as a ≥20% improvement and WRF as a ≥20% deterioration in glomerular filtration rate. Overall, 903 patients met the eligibility criteria, with 31.4% experiencing IRF. Baseline venous congestion/right-side cardiac dysfunction was more common (P ≤ .04) and volume of diuresis (P = .003) was greater in patients with IRF. IRF was associated with a greater incidence of preadmission (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.6-6.7; P < .0001) and postdischarge (OR 1.8, 95% CI 1.2-2.7; P = .006) WRF. IRF was associated with increased mortality (adjusted hazard ratio 1.3, 95% CI, 1.1-1.7; P = .011), a finding largely restricted to patients with postdischarge recurrence of renal dysfunction (P interaction = .038).
IRF is associated with significantly worsened survival and may represent the resolution of venous congestion-induced preadmission WRF. Unlike WRF, the renal dysfunction in IRF patients occurs independently from the confounding effects of acute decongestion and may provide incremental information for the study of cardiorenal interactions.
Journal of cardiac failure 12/2011; 17(12):993-1000. · 3.25 Impact Factor
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ABSTRACT: Renal neurohormonal activation leading to a reduction in glomerular filtration rate (GFR) has been suggested as a mechanism for renal insufficiency (RI) in the setting of heart failure. We hypothesized that RI occurring in the presence of renal neurohormonal activation may be prognostically more important than RI in the absence of renal neurohormonal activation.
Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial (n = 429), Beta-Blocker Evaluation of Survival Trial (BEST) (n = 2691), and Studies Of Left Ventricular Dysfunction (SOLVD) trial (n = 6782) limited datasets were studied. The blood urea nitrogen to creatinine ratio (BUN/Creatinine) was employed as a surrogate for renal neurohormonal activation and the primary outcome was the interaction between BUN/Creatinine and RI associated mortality. Baseline RI (GFR < 60 mL/min/1.73 m²) was associated with mortality in all study populations (P < 0.001). In patients with higher BUN/Creatinine, the risk of mortality was consistently greater in patients with RI [adjusted hazard ratio (HR) ESCAPE = 2.8, 95% confidence interval (CI) 1.3-14.3, P = 0.019; BEST = 1.6, 95% CI 1.2-2.2, P = 0.002; SOLVD = 1.6, 95% CI 1.3-2.0, P = 0.001]. However, in patients with lower BUN/Creatinine, the risk of mortality was not elevated in patients with RI (adjusted HR ESCAPE = 0.94, 95% CI 0.35-2.4, P = 0.90, P interaction = 0.005; BEST = 0.97, 95% CI 0.64-1.4, P = 0.90, P interaction = 0.02; SOLVD = 1.0, 95% CI 0.8-1.3, P = 0.71, P interaction = 0.005).
The association between RI and poor survival observed in heart failure populations appears to be contingent not simply on the presence of a reduced GFR, but possibly on the mechanism by which GFR is reduced.
European Journal of Heart Failure 09/2011; 13(11):1224-30. · 4.90 Impact Factor
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ABSTRACT: Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and gene mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate.
Using a meta-analysis of 28 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, whereas cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern that recapitulates a fetal gene expression program in experimental animal models of HF, human HF microarray studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in end-stage human hearts. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in nonfailing human samples, which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS), thus mimicking gene expression patterns observed in failing samples. Additionally, β-blockers and ACE inhibitor use in end-stage human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity.
Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are a consistent feature in the heterogeneous transcriptional response observed in phenotypically similar models of HF.
Circulation Cardiovascular Genetics 08/2011; 4(5):475-83. · 6.11 Impact Factor
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ABSTRACT: We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF).
Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined.
We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years.
The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes.
Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.
Journal of the American College of Cardiology 07/2011; 58(4):386-94. · 14.16 Impact Factor
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ABSTRACT: The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD).
Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival.
Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality.
In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018).
The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic-associated mortality.
Journal of the American College of Cardiology 07/2011; 58(4):375-82. · 14.16 Impact Factor
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Circulation 07/2011; 124(1):87-94. · 14.74 Impact Factor
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ABSTRACT: Worsening renal function (WRF) commonly complicates the treatment of acute decompensated heart failure. Despite considerable investigation in this area, it remains unclear to what degree WRF is a reflection of treatment- versus patient-related factors. We hypothesized that if WRF is significantly influenced by factors intrinsic to the patient, then WRF during an index hospitalization should predict WRF during subsequent hospitalization.
Consecutive admissions to the Hospital of the University of Pennsylvania with a discharge diagnosis of congestive heart failure were reviewed. Patients with >1 hospitalization were retained for analysis.
In total, 181 hospitalization pairs met the inclusion criteria. Baseline patient characteristics demonstrated significant correlation between hospitalizations (P ≤ .002 for all) but minimal association with WRF. In contrast, variables related to the aggressiveness of diuresis were weakly correlated between hospitalizations but significantly associated with WRF (P ≤ .024 for all). Consistent with the primary hypothesis, WRF during the index hospitalization was strongly associated with WRF during subsequent hospitalization (odds ratio [OR] 2.7, P = .003). This association was minimally altered after controlling for traditional baseline characteristics (OR 2.5, P = .006) and in-hospital treatment-related parameters (OR 2.8, P = .005).
A prior history of WRF is strongly associated with subsequent episodes of WRF, independent of in-hospital treatment received. These results suggest that baseline factors intrinsic to the patient's cardiorenal pathophysiology have substantial influence on the subsequent development of WRF.
American heart journal 05/2011; 161(5):944-9. · 4.65 Impact Factor
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ABSTRACT: Homeodomain only protein x (Hopx) is an unusual homeodomain protein that has diverse effects on cardiac growth. Manipulation of Hopx function in murine models is associated with cardiac hypertrophy, dilation and fibrosis. In the present study, we examined the expression profile of Hopx in various models of pathologic cardiac hypertrophy and failure. Hopx expression is significantly reduced in neonatal rat cardiac myocytes after α/β adrenergic receptor agonist treatment. Cardiac hypertrophy and failure induced by transaortic constriction in mice causes marked down-regulation of Hopx expression. Interestingly, HOPX expression was significantly reduced in hearts of humans with end-stage heart failure when compared to non-failing control hearts, and HOPX levels remain low after LVAD support. Our findings suggest that HOPX/Hopx expression is reduced in multiple examples of human and murine cardiac hypertrophy and failure.
Journal of Molecular and Cellular Cardiology 03/2011; 50(6):1056-8. · 5.17 Impact Factor
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ABSTRACT: Network analysis techniques allow a more accurate reflection of underlying systems biology to be realized than traditional unidimensional molecular biology approaches. Using gene coexpression network analysis, we define the gene expression network topology of cardiac hypertrophy and failure and the extent of recapitulation of fetal gene expression programs in failing and hypertrophied adult myocardium.
We assembled all myocardial transcript data in the Gene Expression Omnibus (n=1617). Because hierarchical analysis revealed species had primacy over disease clustering, we focused this analysis on the most complete (murine) dataset (n=478). Using gene coexpression network analysis, we derived functional modules, regulatory mediators, and higher-order topological relationships between genes and identified 50 gene coexpression modules in developing myocardium that were not present in normal adult tissue. We found that known gene expression markers of myocardial adaptation were members of upregulated modules but not hub genes. We identified ZIC2 as a novel transcription factor associated with coexpression modules common to developing and failing myocardium. Of 50 fetal gene coexpression modules, 3 (6%) were reproduced in hypertrophied myocardium and 7 (14%) were reproduced in failing myocardium. One fetal module was common to both failing and hypertrophied myocardium.
Network modeling allows systems analysis of cardiovascular development and disease. Although we did not find evidence for a global coordinated program of fetal gene expression in adult myocardial adaptation, our analysis revealed specific gene expression modules active during both development and disease and specific candidates for their regulation.
Circulation Cardiovascular Genetics 02/2011; 4(1):26-35. · 6.11 Impact Factor
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Thomas P Cappola,
Scot J Matkovich,
Wei Wang,
Derek van Booven,
Mingyao Li,
Xuexia Wang,
Liming Qu,
Nancy K Sweitzer,
James C Fang,
Muredach P Reilly,
Hakon Hakonarson,
Jeanne M Nerbonne,
Gerald W Dorn
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ABSTRACT: Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K(a) renal chloride channel (ClC-K(a)). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 × 10(-6)). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 × 10(-7)). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K(a) chloride channel currents revealed ≈ 50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis.
Proceedings of the National Academy of Sciences 02/2011; 108(6):2456-61. · 9.68 Impact Factor
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Matthew B Lanktree,
Yiran Guo,
Muhammed Murtaza,
Joseph T Glessner,
Swneke D Bailey,
N Charlotte Onland-Moret,
Guillaume Lettre,
Halit Ongen,
Ramakrishnan Rajagopalan,
Toby Johnson, [......],
Wolfgang Koenig,
Tom R Gaunt,
Sonia S Anand,
Yvonne T van der Schouw,
Nicole Soranzo,
Garret A Fitzgerald,
Alex Reiner,
Robert A Hegele,
Hakon Hakonarson,
Brendan J Keating
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ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
The American Journal of Human Genetics 01/2011; 88(1):6-18. · 10.60 Impact Factor
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Bonnie Ky,
Benjamin French,
Kristin McCloskey,
J Eduardo Rame,
Erin McIntosh,
Puja Shahi,
Daniel L Dries,
W H Wilson Tang,
Alan H B Wu,
James C Fang,
Rebecca Boxer,
Nancy K Sweitzer,
Wayne C Levy,
Lee R Goldberg,
Mariell Jessup, Thomas P Cappola
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ABSTRACT: Soluble ST2 reflects activity of an interleukin-33-dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches.
We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ≤22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B-type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017).
ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.
Circulation Heart Failure 12/2010; 4(2):180-7. · 6.29 Impact Factor
