Authors:
Genesio M. Karere, Jeremy P. Glenn, Shifra Birnbaum, David L. Rainwater, Michael C. Mahaney, John L. VandeBerg, and Laura A Cox
Summary:
Cardiovascular disease (CVD), 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 low-density lipoprotein cholesterol (LDL-C). Here we report differentially regulated hepatic genes that appear to encode 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 7 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 the miRNAs were inversely expressed to the target genes. Candidate gene expression was validated using QRT-PCR and Westerns. This study reveals candidate genes that influence variation in LDL-C in baboons and potential genetic mechanisms for further investigation.
Source:
Journal of Lipid Research; (04/17/13)