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.
Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA.
Pharm Res. 2017 Aug;34(8):1648-1657. doi: 10.1007/s11095-017-2102-x. Epub 2017 Jan 24.
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.
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.
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). 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). 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.
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.
蛋白激酶 Cα（PRKCA）参与多种功能，并与心力衰竭风险和治疗结果有关。本研究旨在鉴定影响人类心脏中 PRKCA 表达的调节变异，并评估其对心脏病的归因风险。
从基因型和组织表达项目（GTEx）中提取 mRNA 表达数量性状基因座（eQTL）。在 51 个人类心脏组织中测量等位基因 mRNA 比率，以鉴定顺式作用的调节变异。用荧光素酶报告基因检测对潜在的调控区域进行检测，并在 GTEx 和全基因组关联研究中进一步评估。
rs9909004（T > C，次要等位基因频率=0.47）位于荧光素酶报告基因检测中具有强大增强子活性的区域，位于在心脏中显示出 PRKCA 强 eQTL 的单体型中（p=1.2×10）。次要 C 等位基因与 PRKCA mRNA 表达降低以及 GWAS 分析中与心力衰竭特征相关的表型风险降低有关（QT 间隔 p=3.0×10）。虽然 rs9909004 可能是调节变异，但不能排除其他处于高度连锁不平衡的变异。不同的调节变异似乎影响其他组织的表达。
携带 rs9909004 的单体型影响心脏中 PRKCA 的表达，与心力衰竭相关的特征有关，可能影响心力衰竭的治疗。
