title: 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; 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Mitchel
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Theusch
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA.
authors.forename: Celia
authors.initials: C
authors.lastname: Cubitt
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA.
authors.forename: Andréa C
authors.initials: AC
authors.lastname: Dosé
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevens
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA.
authors.forename: Devesh
authors.initials: D
authors.lastname: Naidoo
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA. mwmedina@chori.org.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
mesh_terms: D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100 / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000378:metabolism*; D002986:Clinical Trials as Topic; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C573412:LDLR protein, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D011973:Receptors, LDL; C000624389:long non-coding RNA RP1-13D10.2, human; D019821:Simvastatin
keywords: cholesterol; genome-wide association studies; long noncoding RNA; low-density lipoprotein cholesterol; simvastatin