ZNF542P is a pseudogene associated with LDL response to simvastatin treatment

Abstract

Statins are the most commonly prescribed cardiovascular disease drug, but their inter-individual efficacy varies considerably. Genetic factors uncovered to date have only explained a small proportion of variation in low-density lipoprotein cholesterol (LDLC) lowering. To identify novel markers and determinants of statin response, we used whole transcriptome sequence data collected from simvastatin and control incubated lymphoblastoid cell lines (LCLs) established from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. We looked for genes whose statin-induced expression changes were most different between LCLs derived from individuals with high versus low plasma LDLC statin response during the CAP trial. We created a classification model of 82 “signature” gene expression changes that distinguished high versus low LDLC statin response. One of the most differentially changing genes was zinc finger protein 542 pseudogene (ZNF542P), the signature gene with changes most correlated with statin-induced change in cellular cholesterol ester, an in vitro marker of statin response. ZNF542P knock-down in a human hepatoma cell line increased intracellular cholesterol ester levels upon simvastatin treatment. Together, these findings imply a role for ZNF542P in LDLC response to simvastatin and, importantly, highlight the potential significance of noncoding RNAs as a contributing factor to variation in drug response.

Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

“…Simvastatin treatment reduces the risk of cardiovascular events and cardiovascular disease-related deaths, predominantly by decreasing intracellular and circulating cholesterol levels [7,8,9,10]; however, the role of simvastatin in ECs remains unclear. In this study, we found that low simvastatin doses increased the viability of HUVECs while high doses reduced their viability.…”

“…For example, simvastatin suppresses atherosclerotic lesion formation in ApoE KO mice by down-regulating CD36 and calpain-1, thus reducing inflammation [7]. In clinical trials, simvastatin significantly reduced the circulating levels of total cholesterol, LDL-C, VLDL-C, and LDL-C, which are considered risk factors for AS [8,9,10]. Although simvastatin is recognized for its anti-arterial AS effects, the specific mechanism underlying its effects on oxidative stress-induced EC dysfunction remains unclear.…”

Pseudogenes in Cardiovascular Disease

“…They further showed that knock-down of the ZNF542P gene in a human hepatoma cell line increases the intracellular levels of cholesterol ester after the cells were exposed to simvastatin. These findings indicate that ZNF542P may have a role in low-density lipoprotein cholesterol (LDL-C) response to simvastatin (Kim et al, 2018 ). However, since these genes were identified from cell lines, not directly from tissues of patients treated with simvastatin, it is likely that they might not be the most responsive genes in vivo .…”

Identifying Genetic Modulators of Statin Response Using Subject-Derived Lymphoblastoid Cell Lines

“…Using the same approach, but this time with RNA-seq data from both simvastatin and sham-treated CAP LCLs, we sought to identify genes whose statin-induced expression changes were most different between individuals in the tails of the LDL-C statin response distribution. We created a classification model of 82 signature gene expression changes that distinguished high versus low LDL-C statin response [49]. One of the most differentially changing signature genes was ZNF542P, a pseudogene whose expression change was found to be most strongly correlated with statin-induced change in LCL cellular cholesterol ester, an in vitro marker of statin response [49].…”

“…We created a classification model of 82 signature gene expression changes that distinguished high versus low LDL-C statin response [49]. One of the most differentially changing signature genes was ZNF542P, a pseudogene whose expression change was found to be most strongly correlated with statin-induced change in LCL cellular cholesterol ester, an in vitro marker of statin response [49]. These results, together with those for RP1-13D10.2 described above, point to the value of RNA-seq of statin and sham-exposed LCLs for identifying nonprotein coding transcripts with regulatory functions that may contribute to variation in response to statin.…”