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Gene expression profiling to study racial differences after heart transplantation.

ABSTRACT: The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores.We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race.In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels.African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.

SUBMITTER: Khush KK

PROVIDER: S-EPMC4475410 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Gene expression profiling to study racial differences after heart transplantation.

Khush Kiran K KK Pham Michael X MX Teuteberg Jeffrey J JJ Kfoury Abdallah G AG Deng Mario C MC Kao Andrew A Anderson Allen S AS Cotts William G WG Ewald Gregory A GA Baran David A DA Hiller David D Yee James J Valantine Hannah A HA

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20150207 7

<h4>Background</h4>The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a functio ...[more]

PMID: 25840504

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Project description:ObjectivesThe purpose of this study was to assess whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels differ according to race/ethnicity.BackgroundNatriuretic peptides (NP) are hormones with natriuretic, diuretic, and vasodilatory effects. Experimental NP deficiency promotes salt-sensitive hypertension and cardiac hypertrophy, conditions that are more common among black individuals.MethodsWe examined plasma NT-proBNP levels according to race/ethnicity in 3,148 individuals (51% black, 31% white, 18% Hispanic) free of prevalent cardiovascular disease in the Dallas Heart Study. NT-proBNP values in the bottom sex-specific quartile were defined as low. Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates and magnetic resonance imaging measurements of cardiac structure and function.ResultsHypertension was present in 41%, 25%, and 16% of black, white, and Hispanic individuals, respectively. Unadjusted NT-proBNP levels were lowest in black (median: 24 pg/ml; interquartile range [IQR]: 10 to 52 pg/ml) as compared with Hispanic (30 pg/ml; IQR: 14 to 59 pg/ml) and white individuals (32 pg/ml; IQR: 16 to 62 pg/ml), p < 0.0001. In multivariable-adjusted models, black individuals still had significantly lower NT-proBNP levels (-39% [95% confidence interval: -46% to -31%]; p < 0.0001) and greater odds of having low NT-proBNP (odds ratio: 2.46 [95% confidence interval: 1.86 to 3.26]), compared with white individuals. In contrast, NT-proBNP levels did not significantly differ between Hispanic and white individuals (p = 0.28). The finding of lower NT-proBNP levels in black individuals was similar when analyses were restricted to healthy participants without cardiovascular risk factors.ConclusionsIn this multiethnic cohort, NT-proBNP levels differ substantially according to race/ethnicity. Despite a higher prevalence of hypertension, black individuals had significantly lower NP levels than white and Hispanic individuals. A relative NP "deficiency" among black individuals may lead to greater susceptibility to salt retention and hypertension.

Project description:BackgroundSeveral adult stem cell populations exhibit myogenic regenerative potential, thus representing attractive candidates for therapeutic approaches of neuromuscular diseases such as Duchenne Muscular Dystrophy (DMD). We have recently shown that systemic delivery of MuStem cells, skeletal muscle-resident stem cells isolated in healthy dog, generates the remodelling of muscle tissue and gives rise to striking clinical benefits in Golden Retriever Muscular Dystrophy (GRMD) dog. This global effect, which is observed in the clinically relevant DMD animal model, leads us to question here the molecular pathways that are impacted by MuStem cell transplantation. To address this issue, we compare the global gene expression profile between healthy, GRMD and MuStem cell treated GRMD dog muscle, four months after allogenic MuStem cell transplantation.ResultsIn the dystrophic context of the GRMD dog, disease-related deregulation is observed in the case of 282 genes related to various processes such as inflammatory response, regeneration, calcium ion binding, extracellular matrix organization, metabolism and apoptosis regulation. Importantly, we reveal the impact of MuStem cell transplantation on several molecular and cellular pathways based on a selection of 31 genes displaying signals specifically modulated by the treatment. Concomitant with a diffuse dystrophin expression, a histological remodelling and a stabilization of GRMD dog clinical status, we show that cell delivery is associated with an up-regulation of genes reflecting a sustained enhancement of muscle regeneration. We also identify a decreased mRNA expression of a set of genes having metabolic functions associated with lipid homeostasis and energy. Interestingly, ubiquitin-mediated protein degradation is highly enhanced in GRMD dog muscle after systemic delivery of MuStem cells.ConclusionsOverall, our results provide the first high-throughput characterization of GRMD dog muscle and throw new light on the complex molecular/cellular effects associated with muscle repair and the clinical efficacy of MuStem cell-based therapy.

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Gene expression profiling to study racial differences after heart transplantation.

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Gene expression profiling to study racial differences after heart transplantation.

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