title: Identification of candidate genes encoding an LDL-C QTL in baboons.
abstract: Cardiovascular disease (CVD) is the leading cause of death in developed countries, and dyslipidemia is a major risk factor for CVD. We previously identified a cluster of quantitative trait loci (QTL) on baboon chromosome 11 for multiple, related quantitative traits for serum LDL-cholesterol (LDL-C). Here we report differentially regulated hepatic genes encoding an LDL-C QTL that influences LDL-C levels in baboons. We performed hepatic whole-genome expression profiling for LDL-C-discordant baboons fed a high-cholesterol, high-fat (HCHF) diet for seven weeks. We detected expression of 117 genes within the QTL 2-LOD support interval. Three genes were differentially expressed in low LDL-C responders and 8 in high LDL-C responders in response to a HCHF diet. Seven genes (ACVR1B, CALCOCO1, DGKA, ERBB3, KRT73, MYL6B, TENC1) showed discordant expression between low and high LDL-C responders. To prioritize candidate genes, we integrated miRNA and mRNA expression profiles using network tools and found that four candidates (ACVR1B, DGKA, ERBB3, TENC1) were miRNA targets and that the miRNAs were inversely expressed to the target genes. Candidate gene expression was validated using QRT-PCR and Western blotting. This study reveals candidate genes that influence variation in LDL-C in baboons and potential genetic mechanisms for further investigation.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute , San Antonio, TX 78227, USA.
authors.forename: Genesio M
authors.initials: GM
authors.lastname: Karere
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Glenn
authors.forename: Shifra
authors.initials: S
authors.lastname: Birnbaum
authors.forename: Sassan
authors.initials: S
authors.lastname: Hafizi
authors.forename: David L
authors.initials: DL
authors.lastname: Rainwater
authors.forename: Michael C
authors.initials: MC
authors.lastname: Mahaney
authors.forename: John L
authors.initials: JL
authors.lastname: VandeBerg
authors.forename: Laura A
authors.initials: LA
authors.lastname: Cox
mesh_terms: D000818:Animals; D015153:Blotting, Western; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D020869:Gene Expression Profiling; D010215:Papio / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D008078:Cholesterol, LDL; D012333:RNA, Messenger
keywords: cardiovascular disease; diet-responsive liver gene expression; dyslipidemia; low density lipoprotein-cholesterol