Grant Gemma R, Robinson Susan W, Edwards Richard E, Clothier Bruce, Davies Reginald, Judah David J, Broman Karl W, Smith Andrew G
MRC Toxicology Unit, University of Leicester, Leicester, UK.
Hepatology. 2006 Jul;44(1):174-85. doi: 10.1002/hep.21233.
Polymorphisms of genes linked to iron metabolism may account for individual variability in hemochromatosis and iron status connected with liver and cardiovascular diseases, cancers, toxicity, and infection. Mouse strains exhibit marked differences in levels of non-heme iron, with C57BL/6J and SWR showing low and high levels, respectively. The genetic basis for this variability was examined using quantitative trait loci (QTL) analysis together with expression profiling and chromosomal positions of known iron-related genes. Non-heme iron levels in liver and spleen of C57BL/6J x SWR F2 mice were poorly correlated, indicating independent regulation. Highly significant (P < .01) polymorphic loci were found on chromosomes 2 and 16 for liver and on chromosomes 8 and 9 for spleen. With sex as a covariate, additional significant or suggestive (P < 0.1) QTL were detected on chromosomes 7, 8, 11, and 19 for liver and on chromosome 2 for spleen. A gene array showed no clear association between most loci and differential iron-related gene expression. The gene for transferrin and a transferrin-like gene map close to the QTL on chromosome 9. Transferrin saturation was significantly lower in C57BL/6J mice than in SWR mice, but there was no significant difference in the serum level of transferrin, hepatic expression, or functional change in cDNA sequence. beta2-Microglobulin, which, unlike other loci, was associated with C57BL/6J alleles, is a candidate for the chromosome 2 QTL for higher iron. In conclusion, the findings show the location of polymorphic genes that determine basal iron status in wild-type mice. Human equivalents may be pertinent in predisposition to hepatic and other disorders.
与铁代谢相关的基因多态性可能是导致血色素沉着症个体差异以及与肝脏和心血管疾病、癌症、毒性和感染相关的铁状态个体差异的原因。小鼠品系在非血红素铁水平上表现出显著差异，C57BL/6J和SWR分别呈现低水平和高水平。利用数量性状基因座（QTL）分析以及已知铁相关基因的表达谱和染色体位置，研究了这种差异的遗传基础。C57BL/6J×SWR F2小鼠肝脏和脾脏中的非血红素铁水平相关性较差，表明存在独立调节。在肝脏的2号和16号染色体以及脾脏的8号和9号染色体上发现了高度显著（P <.01）的多态性位点。以性别作为协变量，在肝脏的7号、8号、11号和19号染色体以及脾脏的2号染色体上检测到了其他显著或提示性（P < 0.1）的QTL。基因阵列显示，大多数位点与铁相关基因的差异表达之间没有明显关联。转铁蛋白基因和一个类似转铁蛋白的基因位于9号染色体上靠近QTL的位置。C57BL/6J小鼠的转铁蛋白饱和度显著低于SWR小鼠，但转铁蛋白的血清水平、肝脏表达或cDNA序列的功能变化没有显著差异。与其他位点不同，β2-微球蛋白与C57BL/6J等位基因相关，是2号染色体上高铁QTL的候选基因。总之，这些发现表明了在野生型小鼠中决定基础铁状态的多态性基因的位置。人类中的等效基因可能与肝脏和其他疾病的易感性相关。
