Liver Center and Gastroenterology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Gastroenterol Clin North Am. 2010 Jun;39(2):185-207, vii-viii. doi: 10.1016/j.gtc.2010.02.007.
Epidemiologic investigations, clinical observations, and family and twin studies in humans, as well as gallstone prevalence investigations in inbred mouse models, support the concept that cholesterol cholelithiasis could result from a complex interaction of environmental factors and the effects of multiple undetermined genes. Quantitative trait locus (QTL) analysis is a powerful genetic method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes, and the subsequent positional cloning of such genes responsible for QTLs, followed by the use of manufactured mouse strains with "knockout" or "knockin" of the genes, could lead to the discovery of lithogenic actions of gallstone (LITH) genes. The combined use of genomic strategies and phenotypic studies in inbred strains of mice has successfully resulted in the identification of many candidate LITH genes. Because there is exceptionally close homology between mouse and human genomes, the orthologous human LITH genes can be identified from the mouse study. The discovery of LITH genes and more fundamental knowledge concerning the genetic determinants and molecular mechanisms underlying the formation of cholesterol gallstones in humans will pave the way for critical diagnostic and prelithogenic preventive measures for this exceptionally prevalent digestive disease.
流行病学研究、临床观察、人类的家族和双胞胎研究，以及同系小鼠模型中的胆结石患病率研究，都支持胆固醇性胆石症可能是由环境因素与多种未确定基因的作用的复杂相互作用引起的概念。数量性状基因座（QTL）分析是一种强大的遗传方法，可用于识别主要限速遗传缺陷，并将其与主要基因突变引起的继发性下游成石作用区分开来，随后对负责 QTL 的这些基因进行定位克隆，然后使用“敲除”或“敲入”这些基因的人工制造小鼠品系，可能会发现胆结石（LITH）基因的成石作用。基因组策略和同系小鼠品系中的表型研究的联合使用已成功鉴定出许多候选 LITH 基因。由于小鼠和人类基因组之间具有极高的同源性，因此可以从小鼠研究中鉴定出同源的人类 LITH 基因。LITH 基因的发现以及有关胆固醇胆结石形成的遗传决定因素和分子机制的更基本的知识，将为这种极其普遍的消化疾病的关键诊断和前成石预防措施铺平道路。
