title: Regulatory Variants Modulate Protein Kinase C α (PRKCA) Gene Expression in Human Heart.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 1005 BRT, 460 West 12th Ave, Columbus, Ohio, 43210, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 1005 BRT, 460 West 12th Ave, Columbus, Ohio, 43210, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.affiliation: Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 1005 BRT, 460 West 12th Ave, Columbus, Ohio, 43210, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.affiliation: Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 1005 BRT, 460 West 12th Ave, Columbus, Ohio, 43210, USA. wang.808@osu.edu.|Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 1005 BRT, 460 W 12th Avenue, Columbus, Ohio, 43210, USA. wang.808@osu.edu.
authors.forename: Danxin
authors.identifier: http://orcid.org/0000-0002-7134-3065
authors.initials: D
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006331:Heart Diseases / Q000235:genetics*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051571:Protein Kinase C-alpha
keywords: association; gene expression; genetic variant; heart failure; polymorphism; protein kinase C α (PRKCA)