Dataset Information

Association of Regulatory Genetic Variants for Protein Kinase C? with Mortality and Drug Efficacy in Patients with Heart Failure.

ABSTRACT: PURPOSE:Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T???C] and rs9303504 [C???G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown. METHODS:Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n?=?951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models. RESULTS:The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR?=?0.81 (95% CI?=?0.67-0.98), p?=?0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p?>?0.1 for all). CONCLUSIONS:A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.

SUBMITTER: Luzum JA

PROVIDER: S-EPMC7197488 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Association of Regulatory Genetic Variants for Protein Kinase Cα with Mortality and Drug Efficacy in Patients with Heart Failure.

Luzum Jasmine A JA Ting Christopher C Peterson Edward L EL Gui Hongsheng H Shugg Tyler T Williams L Keoki LK Li Liang L Sadee Wolfgang W Wang Danxin D Lanfear David E DE

Cardiovascular drugs and therapy 20191201 6

<h4>Purpose</h4>Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown.<h4>Methods</h4>Patients with HF in a prospective registry starting in 2007 were genotyped by whole ...[more]

PMID: 31728800

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Project description:Despite the administration of multiple drugs that are highly effective in vitro, tuberculosis (TB) treatment requires prolonged drug administration and is confounded by the emergence of drug-resistant strains. To understand the mechanisms that limit antibiotic efficacy, we performed a comprehensive genetic study to identify Mycobacterium tuberculosis genes that alter the rate of bacterial clearance in drug-treated mice. Several functionally distinct bacterial genes were found to alter bacterial clearance, and prominent among these was the glpK gene that encodes the glycerol-3-kinase enzyme that is necessary for glycerol catabolism. Growth on glycerol generally increased the sensitivity of M. tuberculosis to antibiotics in vitro, and glpK-deficient bacteria persisted during antibiotic treatment in vivo, particularly during exposure to pyrazinamide-containing regimens. Frameshift mutations in a hypervariable homopolymeric region of the glpK gene were found to be a specific marker of multidrug resistance in clinical M. tuberculosis isolates, and these loss-of-function alleles were also enriched in extensively drug-resistant clones. These data indicate that frequently observed variation in the glpK coding sequence produces a drug-tolerant phenotype that can reduce antibiotic efficacy and may contribute to the evolution of resistance.IMPORTANCE TB control is limited in part by the length of antibiotic treatment needed to prevent recurrent disease. To probe mechanisms underlying survival under antibiotic pressure, we performed a genetic screen for M. tuberculosis mutants with altered susceptibility to treatment using the mouse model of TB. We identified multiple genes involved in a range of functions which alter sensitivity to antibiotics. In particular, we found glycerol catabolism mutants were less susceptible to treatment and that common variation in a homopolymeric region in the glpK gene was associated with drug resistance in clinical isolates. These studies indicate that reversible high-frequency variation in carbon metabolic pathways can produce phenotypically drug-tolerant clones and have a role in the development of resistance.

Project description:Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p < 1 × 10-5 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci. Methods: We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases (N = 12) and control groups of patients treated with anthracycline +/- trastuzumab without HF (N = 282) and patients with HF that were never treated with anthracycline or trastuzumab (N = 690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6. Results: TRPC6 5' flanking variant rs57242572-T was significantly more frequent in cases compared to controls, p = 0.031, and rs61918162-T showed a trend for association, p = 0.065. The rs61918162 T-allele was associated with higher TRPC6 expression in the heart left ventricle. We identified a single TRPC6 rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction. Conclusions: Genetic variants that are associated with increased TRPC6 expression in the heart and rare TRPC6 missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.

Dataset Information

Association of Regulatory Genetic Variants for Protein Kinase C? with Mortality and Drug Efficacy in Patients with Heart Failure.

Publications

Association of Regulatory Genetic Variants for Protein Kinase Cα with Mortality and Drug Efficacy in Patients with Heart Failure.

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