Abstract
Background: Dyslipidemia is central to the definition of metabolic syndrome (MS), one of most prevalent human diseases worldwide. We preformed genome-wide association study (GWAS) of triacylglycerols (TG) and cholesterol (C) distribution into lipoprotein fractions in the recombinant inbred strain panel PXO (segregating alleles of two MS models, SHR and PD strains, together with those of normolipidemic Brown Norway strain origin), followed by transcriptomic and miRNomic (microRNA profiling) analyses. Methods: We established morphometric and metabolic profile in adult male rats of 14 PXO strains and two progenitor strains (n=183) including glucose tolerance and TG and C concentrations in 20 lipoprotein fractions. GWAS utilizing >20,000 SNPs was performed using MapManager, the significance validated by 2000 permutations per trait. The hepatic transcriptome and miRNome profiles of the most contrasting strains were generated using Affymetrix GeneAtlas system followed by network analysis (Ingenuity Pathway Analysis). Results: We have identified 14 haplotype blocks showing suggestive or significant linkage to studied traits. Except for LDL-TG loci on chromosomes 3 and 12, PXO strains carrying the SHR allele displayed significantly higher values of the lipid linked traits, e.g. LDL-C (21.2±0.4 vs. 12.5±0.4 mg/dl in PXO strains with SHR allele vs. BXH2 allele). C concentrations in large, medium and very small LDL particles were significantly associated to a single gene ( Lrp1b ). Subsequent transcriptomic comparison of phenotypically most contrasting identified series of dysregulated metabolic and signaling pathways including cholesterol biosynthesis and the key upstream regulators such as HNF1 , HNF4 and PPARA . Conclusion: We identified several novel variants associated to TG and C concentrations in lipoprotein fractions together with their transcriptomic and biological network correlates.
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