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RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.

ABSTRACT: Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies; however, identifying the molecular mechanism underlying these associations is not straightforward. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of rosuvastatin users identified a sub-genome-wide association of rs6924995, a single-nucleotide polymorphism ?10 kb downstream of myosin regulatory light chain interacting protein (MYLIP, aka IDOL and inducible degrader of low-density lipoprotein receptor [LDLR]), with LDL cholesterol statin response. Interestingly, although this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA.Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial, we found that statin-induced change in RP1-13D10.2 levels differed between cell lines from the tails of the white and black low-density lipoprotein cholesterol response distributions, whereas no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of apolipoprotein B. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 A versus G allele and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP lymphoblastoid cell lines. Finally, RP1-13D10.2 expression levels seem to be sterol regulated, consistent with its potential role as a novel lipid regulator.RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to low-density lipoprotein cholesterol response to statin treatment. These findings highlight the potential role of noncoding RNAs as determinants of interindividual variation in drug response.

SUBMITTER: Mitchel K

PROVIDER: S-EPMC4917428 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.

Mitchel Katrina K Theusch Elizabeth E Cubitt Celia C Dosé Andréa C AC Stevens Kristen K Naidoo Devesh D Medina Marisa W MW

Circulation. Cardiovascular genetics 20160412 3

<h4>Background</h4>Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies; however, identifying the molecular mechanism underlying these associations is not straightforward. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of rosuvastatin users identified a sub-genome-wide association of rs6924995, a single-nucleotide polymorphism ≈10 kb downstream of my ...[more]

PMID: 27071970

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Project description:Although statin drugs are generally efficacious for lowering plasma LDL-cholesterol levels, there is considerable variability in response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approach that was applied to 10,149 genes expressed in immortalized lymphoblastoid cell lines (LCLs) derived from 480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR, a key regulator of cellular cholesterol metabolism and the target of statin inhibition. This analysis yielded 45 genes, from which RHOA was selected for follow-up because it has been found to participate in mediating the pleiotropic but not the lipid-lowering effects of statin treatment. RHOA knock-down in hepatoma cell lines reduced HMGCR, LDLR, and SREBF2 mRNA expression and increased intracellular cholesterol ester content as well as apolipoprotein B (APOB) concentrations in the conditioned media. Furthermore, inter-individual variation in statin-induced RHOA mRNA expression measured in vitro in CAP LCLs was correlated with the changes in plasma total cholesterol, LDL-cholesterol, and APOB induced by simvastatin treatment (40 mg/d for 6 wk) of the individuals from whom these cell lines were derived. Moreover, the minor allele of rs11716445, a SNP located in a novel cryptic RHOA exon, dramatically increased inclusion of the exon in RHOA transcripts during splicing and was associated with a smaller LDL-cholesterol reduction in response to statin treatment in 1,886 participants from the CAP and Pravastatin Inflamation and CRP Evaluation (PRINCE; pravastatin 40 mg/d) statin clinical trials. Thus, an unbiased filter approach based on transcriptome-wide profiling identified RHOA as a gene contributing to variation in LDL-cholesterol response to statin, illustrating the power of this approach for identifying candidate genes involved in drug response phenotypes.

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RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.

Publications

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.

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