Hodúlová Miloslava, Šedová Lucie, Křenová Drahomíra, Liška František, Krupková Michaela, Kazdová Ludmila, Tremblay Johanne, Hamet Pavel, Křen Vladimír, Šeda Ondřej
Institute of Biology and Medical Genetics, the First Faculty of Medicine, Charles University and the General Teaching Hospital, Prague, Czech Republic; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Institute of Biology and Medical Genetics, the First Faculty of Medicine, Charles University and the General Teaching Hospital, Prague, Czech Republic.
PLoS One. 2014 Oct 8;9(10):e109983. doi: 10.1371/journal.pone.0109983. eCollection 2014.
The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8-13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains.
主要脂蛋白类别的血浆谱及其细分为特定组分在动脉粥样硬化的发病机制中起着关键作用，并且是冠状动脉疾病的主要预测指标。我们的目的是在重组近交系大鼠组PXO中确定甘油三酯和胆固醇在脂蛋白组分及脂蛋白颗粒大小中的分布的基因组决定因素，在该组中，两种代谢综合征大鼠模型（SHR和PD近交系）的等位基因与来自挪威棕色大鼠品系的等位基因一起分离。对15个PXO品系（每个品系n = 8 - 13）的成年雄性大鼠以及两个祖系SHR - Lx（n = 13）和BXH2/Cub（n = 18）进行为期一周的高糖饮食喂养。我们利用704个多态性微卫星标记对20个脂蛋白组分中的甘油三酯（TG）和胆固醇（C）浓度以及主要脂蛋白颗粒类别大小进行了关联分析，每个性状通过2000次置换验证全基因组显著性。随后使用超过20000个单核苷酸多态性图谱对鉴定出的数量性状位点进行了电子定位。在大多数表型中，我们在品系间鉴定出了显著的梯度（例如，极低密度脂蛋白甘油三酯从5.6至66.7mg/dl）。我们在大鼠染色体3、4、7、8、11和12上鉴定出14个位点（包含1至65个基因），这些位点与一个或多个研究性状显示出提示性或显著关联。携带SHR等位基因的PXO品系除低密度脂蛋白甘油三酯和肥胖指数外，相关性状的值显著更高。大、中、非常小的低密度脂蛋白颗粒中的胆固醇浓度与跨越单个基因低密度脂蛋白受体相关蛋白1B（Lrp1b）一部分的单倍型块显著相关。通过全基因组关联分析，我们在大鼠模型品系的重组近交系中鉴定出了甘油三酯和胆固醇在脂蛋白组分中分布的新的遗传决定因素。
