Wittenburg H, Lyons M A, Paigen B, Carey M C
Department of Medicine, Harvard Medical School, Gastroenterology Division, Brigham and Women's Hospital, and Harvard Digestive Diseases Center, Boston, MA 02115, USA.
Dig Liver Dis. 2003 Jul;35 Suppl 3:S2-7. doi: 10.1016/s1590-8658(03)00085-9.
The individual risk for developing cholesterol gallstones in response to specific environmental factors is determined by complex genetics involving multiple genes. In this review, we introduce inbred mice as a model to localise and identify the murine genes that harbour cholesterol gallstone susceptibility alleles (Lith genes). These genes are associated with increased risk of gallstone formation when mice are fed a lithogenic diet containing cholesterol and cholic acid. We summarise the steps involved in localising the chromosomal regions that harbour Lith genes, focusing particularly on the initial step known as quantitative trait locus mapping, which employs breeding crosses of gallstone-susceptible and gallstone-resistant inbred mouse strains. Subsequent steps to narrow the chromosomal regions of the quantitative trait loci and identify the underlying Lith genes are outlined, with particular reference to the examples of Lith1 and Lith2, the first discovered quantitative trait loci associated with murine cholesterol cholelithiasis. We have now reported five quantitative trait loci for murine cholelithogenesis, which are officially named Lith1 through Lith5. Once the genes underlying these quantitative trait loci and other chromosomal loci from ongoing mouse crosses are identified and confirmed, the 'road-map' for discovery of orthologous human LITH genes will be available and, thereafter, their putative roles in cholesterol gallstone formation can be tested in selected human populations.
个体因特定环境因素而患胆固醇胆结石的风险是由涉及多个基因的复杂遗传学决定的。在本综述中，我们引入近交系小鼠作为模型，以定位和鉴定携带胆固醇胆结石易感等位基因（Lith基因）的小鼠基因。当给小鼠喂食含有胆固醇和胆酸的致石性饮食时，这些基因与胆结石形成风险增加有关。我们总结了定位携带Lith基因的染色体区域所涉及的步骤，特别关注称为数量性状基因座定位的初始步骤，该步骤采用胆结石易感和抗胆结石近交系小鼠品系的杂交育种。概述了缩小数量性状基因座染色体区域并鉴定潜在Lith基因的后续步骤，特别参考了Lith1和Lith2的例子，这是首次发现的与小鼠胆固醇结石病相关的数量性状基因座。我们现已报道了五个小鼠胆石形成的数量性状基因座，它们被正式命名为Lith1至Lith5。一旦确定并确认了这些数量性状基因座以及正在进行的小鼠杂交中的其他染色体位点的潜在基因，发现直系同源人类LITH基因的“路线图”将可用，此后，可以在选定的人群中测试它们在胆固醇胆结石形成中的假定作用。
