title: Impact of Statins on Gene Expression in Human Lung Tissues.
abstract: Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up-regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta-analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin users with chronic lung diseases do not seem to be mediated through direct regulation of gene expression in the lung.
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lane
authors.affiliation: University of British Columbia, Department of Medicine & Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
authors.forename: Stephan F
authors.initials: SF
authors.lastname: van Eeden
authors.affiliation: University of British Columbia, Department of Medicine & Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.affiliation: University of British Columbia, Department of Medicine & Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: University of British Columbia, Department of Medicine & Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.|The PROOF Centre of Excellence, Vancouver, Canada.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Tebbutt
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: University of British Columbia, Department of Medicine & Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Canada.|Department of Molecular Medicine, Laval University, Quebec City, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger