title: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner.
abstract: Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR=15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho=0.32, q=0.11) was driven by men (interaction P=0.0055). rs73161338 was associated with INSIG1 expression changes (P=5.4 × 10-5) and TG response in two statin clinical trials (P=0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P=5.6 × 10-6). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Theusch
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Stevens
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
authors.forename: Y-D I
authors.initials: YI
authors.lastname: Chen
authors.affiliation: Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Medina
mesh_terms: D000328:Adult; D000368:Aged; D002460:Cell Line; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D012737:Sex Factors; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D014280:Triglycerides; D019821:Simvastatin