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

  • Liang Li
  • Lizhi Zhang
  • Philip F. Binkley
  • Wolfgang Sadee
  • Danxin Wang
Research Paper

DOI: 10.1007/s11095-017-2102-x

Cite this article as:
Li, L., Zhang, L., Binkley, P.F. et al. Pharm Res (2017). doi:10.1007/s11095-017-2102-x
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Abstract

Purpose

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.

KEY WORDS

association gene expression genetic variant heart failure polymorphism protein kinase C α (PRKCA) 

Abbreviations

ADRB1

beta-1 adrenergic receptor

AEI

Allelic expression imbalance

eQTL

Expression quantitative trait loci

GTEx

Genotype-Tissue Expression

GWAS

Genome-wide association studies

LD

Linkage disequilibrium

MAF

Minor allele frequency

PLB

Phospholamban

PRKCA

Protein kinase C α subunit

SERCA-2

Sarcoplasmic reticulum Ca2+ ATPase-2

SNPs

Single nucleotide polymorphisms

TF

Transcription factors

Supplementary material

11095_2017_2102_MOESM1_ESM.docx (23 kb)
ESM 1(DOCX 22 kb)

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of MedicineThe Ohio State UniversityColumbusUSA
  2. 2.Department of Internal Medicine, College of MedicineThe Ohio State UniversityColumbusUSA
  3. 3.Center for Pharmacogenomics and Department of Cancer Biology and Genetics, College of MedicineThe Ohio State UniversityColumbusUSA

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