Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
J Lipid Res. 2010 Oct;51(10):2929-39. doi: 10.1194/jlr.M005686. Epub 2010 Jul 22.
Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 x 10(-9)). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 x 10(-14)) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet.
个体血浆胆固醇水平因饮食而有很大差异。然而，影响这种反应的基因在很大程度上是未知的。喂食动脉粥样硬化饮食的灰色短尾负鼠的非高密度脂蛋白（V+LDL）胆固醇水平差异很大，我们之前报道过两个数量性状基因座（QTL）影响两种饮食中的 V+LDL 胆固醇。我们使用无假设的全基因组连锁分析，对 325 只纯种负鼠的数据进行分析，在负鼠 1q 染色体上定位到一个 V+LDL 胆固醇的 QTL [对数优势（LOD）= 3.11，基因组 P = 0.019]，在动脉粥样硬化饮食（即高胆固醇和高脂肪）上定位到另一个 V+LDL 胆固醇的 QTL （LOD = 9.88，基因组 P = 5 x 10(-9)）。然后，我们采用了一种新的策略，涉及联合分析基因组资源、表达分析、测序和基因分型，以鉴定 8 号染色体 QTL 的候选基因。ABCB4 中的一个多态性与高胆固醇、高脂肪饮食中的血浆 V+LDL 胆固醇浓度密切相关（P = 9 x 10(-14)）。这项研究的结果表明，ABCB4 或紧密连锁基因的遗传变异是负鼠对动脉粥样硬化饮食的 V+LDL 胆固醇反应差异的原因。
