The pathophysiology of gallstone disease in humans seems to be complex and more genes are likely to be discovered. Due to the limitations of genetic manipulations in humans, important conclusions about disease related genes are being derived from the animal models. However, methods for studying complex traits like gallstone disease differ from those used to discover genes for simple Mendelian defects. Using a genetic technique called quantitative trait analysis (QTL) with the help of variable DNA sequences (micro satellites), mice genes relevant to gallstone susceptibility have been mapped. The genome-wide search has resulted in identification of several candidate genes, which are involved in gallstone formation in mice. [33] In humans, QTL analysis of affected sib-pairs or families is restricted due to multiple modes of inheritance of the trait, incomplete penetrance, genetic heterogeneity and a large variation in environmental conditions. In mice, different in-bred strains are available which differ in their susceptibility to gallstone formation when kept on synthetic diet containing 1% cholesterol and 0.5% colic acid. The inter-strain differences in gallstone formation in mice can be utilised for QTL analysis. The method involves experimental crosses between inbred strains with different susceptibility and quantification of gallstones in second-generation progeny. These data are statistically correlated with microsatellite genetic markers spaced at 15 cM interval in the entire mice genome. Using combined genomic strategies and phenotypic studies in mice; several QTL regions for gallstone susceptibility have been identified. As expected, some of the candidate genes in the QTL belong to classic rate-limiting enzymes of cholesterol metabolism. Other prominent candidate genes responsible for cholesterol gallstones in mice (lith genes) identified so far have been shown to code for hepatic regulatory enzymes (Hmgcr, Cypa1, Soat2), cholecystokinin receptor (Cckar), HDL receptor (Srb1), apolipoproteins (ApoE), basolateral transporters for organic cation (Slc22a1) and canaliculus export pump for bile salts (Abcb11).[34],[35],[36] Presently, many of their human orthologs (LITH genes) are being evaluated for their roles in gallstone formation in humans.[33] Therefore, the genetic study of lith genes in mice models not only proves classic paradigms in gallstone disease (super-saturation of biliary cholesterol), but also paves the way for the identification of novel genes, which may also play crucial role in pathophysiology of gallstone disease. These developments are certainly going to accelerate the discovery of new targets for rational drug design and dietary interventions.
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