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

Abstract

Background Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies (GWAS); however, identifying the molecular mechanism underlying these associations is not straightforward. The JUPITER trial of rosuvastatin users identified a sub-genome wide association of rs6924995, a SNP ~10kb downstream of MYLIP (aka IDOL, inducible degrader of LDLR), with LDL cholesterol statin response. Interestingly, though this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA. Methods and Results Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics simvastatin clinical trial, we found that statin induced change in RP1-13D10.2 levels differed between cell lines from the tails of the Caucasian and African American LDLC response distributions, while 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 APOB. 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” vs. “G” allele, and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP LCLs. Lastly, RP1-13D10.2 expression levels appear to be sterol regulated, consistent with its potential role as a novel lipid regulator. Conclusions RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to LDLC response to statin treatment. These findings highlight the potential role of non-coding RNAs as determinants of inter-individual variation in drug response.

Lnc-ing Common Polymorphisms to Statin Responsiveness at the MYLIP Locus

“…This work follows several other examples of noncoding RNAs such as miRNAs that regulate both cholesterol efflux and LDL-C uptake in vivo, such as miR-33, miR-148a, and others, 10 as well as fewer examples of lncRNAs that have been shown to regulate lipoprotein metabolism. 11 However, this study by Mitchel et al 6 is among the first to show a genetic polymorphism within a lncRNA that modulates its expression and affects its downstream effects with regard to lipid homeostasis.…”

“…A report by Mitchel et al 6 in this issue of Circulation Cardiovascular Genetics highlights this complexity in an effort to identify the mechanism governing the association of a SNP, rs6924995, at the MYLIP gene locus to statin responsiveness in LDL-C lowering. The authors explored the mechanism governing the sub-GWAS significant association of a SNP identified in a previous GWAS for statin effects on LDL-C lowering by the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) investigators.…”

“…However, the SNP itself lies within a processed pseudogene, RP1-13D10.2. Given that some such pseudogenes are more recently being revealed as encoding long noncoding RNAs (lncRNAs), Mitchel et al 6 sought to address the possibility that RP1-13D10.2 is indeed a lncRNA and that it may directly mediate an effect conferred by the SNP on LDL-C levels in response to statins.…”

“…The study by Mitchel et al 6 provides an example of the complexity of mechanisms by which noncoding variants may regulate gene expression and associate with multifactorial traits, such as drug responsiveness and plasma lipids. Here, a SNP was identified in relatively close proximity (≈10 kb) to a gene with plausible and demonstrated roles in influencing the associated trait.…”

“…The studies by Mitchel et al 6 suggest that MYLIP is unlikely to be regulated by the rs6924995 SNP because of the lack of finding of a difference in MYLIP gene expression in the lymphoblastoid cell lines from high versus low responders to statins among the cell lines tested. However, given that statins primarily act to regulate LDL-C levels in the liver in humans, a human hepatocyte cell line would be a more appropriate model for evaluating the impact of the SNP on the regulation of expression of genes that may be involved in determining the statin response.…”