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Regulatory Variants Modulate Protein Kinase C ? (PRKCA) Gene Expression in Human Heart.

ABSTRACT: PURPOSE:Protein kinase C ? (PRKCA) is involved in multiple functions and has been implicated in heart failure risks and treatment outcomes. This study aims to identify regulatory variants affecting PRKCA expression in human heart, and evaluate attributable risk of heart disease. METHODS:mRNA expression quantitative trait loci (eQTLs) were extracted from the Genotype and Tissue Expression Project (GTEx). Allelic mRNA ratios were measured in 51 human heart tissues to identify cis-acting regulatory variants. Potential regulatory regions were tested with luciferase reporter gene assays and further evaluated in GTEx and genome-wide association studies. RESULTS:Located in a region with robust enhancer activity in luciferase reporter assays, rs9909004 (T?>?C, minor allele frequency =0.47) resides in a haplotype displaying strong eQTLs for PRKCA in heart (p?=?1.2?×?10-23). The minor C allele is associated with both decreased PRKCA mRNA expression and decreased risk of phenotypes characteristic of heart failure in GWAS analyses (QT interval p?=?3.0?×?10-14). While rs9909004 is the likely regulatory variant, other variants in high linkage disequilibrium cannot be excluded. Distinct regulatory variants appear to affect expression in other tissues. CONCLUSIONS:The haplotype carrying rs9909004 influences PRKCA expression in the heart and is associated with traits linked to heart failure, potentially affecting therapy of heart failure.

SUBMITTER: Li L

PROVIDER: S-EPMC7315374 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Regulatory Variants Modulate Protein Kinase C α (PRKCA) Gene Expression in Human Heart.

Li Liang L Zhang Lizhi L Binkley Philip F PF Sadee Wolfgang W Wang Danxin D

Pharmaceutical research 20170124 8

<h4>Purpose</h4>Protein kinase C α (PRKCA) is involved in multiple functions and has been implicated in heart failure risks and treatment outcomes. This study aims to identify regulatory variants affecting PRKCA expression in human heart, and evaluate attributable risk of heart disease.<h4>Methods</h4>mRNA expression quantitative trait loci (eQTLs) were extracted from the Genotype and Tissue Expression Project (GTEx). Allelic mRNA ratios were measured in 51 human heart tissues to identify cis-ac ...[more]

PMID: 28120175

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Project description:BackgroundStatins are widely prescribed to lower plasma low-density lipoprotein cholesterol levels. Though statins reduce cardiovascular disease risk overall, statin efficacy varies, and some people experience adverse side effects while on statin treatment. Statins also have pleiotropic effects not directly related to their cholesterol-lowering properties, but the mechanisms are not well understood. To identify potential genetic modulators of clinical statin response, we looked for genetic variants associated with statin-induced changes in gene expression (differential eQTLs or deQTLs) in lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial. We exposed CAP LCLs to 2 μM simvastatin or control buffer for 24 h and performed polyA-selected, strand-specific RNA-seq. Statin-induced changes in gene expression from 259 European ancestry or 153 African American ancestry LCLs were adjusted for potential confounders prior to association with genotyped and imputed genetic variants within 1 Mb of each gene's transcription start site.ResultsFrom the deQTL meta-analysis of the two ancestral populations, we identified significant cis-deQTLs for 15 genes (TBC1D4, MDGA1, CHI3L2, OAS1, GATM, ASNSD1, GLUL, TDRD12, PPIP5K2, OAS3, SERPINB1, ANKDD1A, DTD1, CYFIP2, and GSDME), eight of which were significant in at least one of the ancestry subsets alone. We also conducted eQTL analyses of the endogenous (control-treated), statin-treated, and average of endogenous and statin-treated LCL gene expression levels. We identified eQTLs for approximately 6000 genes in each of the three (endogenous, statin-treated, and average) eQTL meta-analyses, with smaller numbers identified in the ancestral subsets alone.ConclusionsSeveral of the genes in which we identified deQTLs have functions in human health and disease, such as defense from viruses, glucose regulation, and response to chemotherapy drugs. This suggests that DNA variation may play a role in statin effects on various health outcomes. These findings could prove useful to future studies aiming to assess benefit versus risk of statin treatment using individual genetic profiles.

Dataset Information

Regulatory Variants Modulate Protein Kinase C ? (PRKCA) Gene Expression in Human Heart.

Publications

Regulatory Variants Modulate Protein Kinase C α (PRKCA) Gene Expression in Human Heart.

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