Cholesterol Gallstone Susceptibility Loci: A Mouse Map, Candidate Gene Evaluation, and Guide to Human LITH Genes

Abstract

Cholesterol gallstones are prevalent and costly, chiefly among developed countries. In addition to numerous environmental risk factors, a complex genetic basis determines the risk for developing cholesterol gallstones. Rather than monogenic mutations that are rare and occur in limited populations, genetic predisposition to gallstone susceptibility in general populations arises from polymorphisms in multiple genes, each making a small contribution to overall risk. Because mouse and human genomes are conserved and only a critical subset of homologous genes appears rate limiting for gallstone susceptibility in these species, a genetic map of mouse lithogenic ( Lith ) loci provides a roadmap for the discovery of human LITH genes. Quantitative trait locus (QTL) mapping was employed to identify Lith loci in mice. Repeated detection of colocalizing QTLs among 9 crosses of 12 genetically diverse progenitor strains suggests identification of most major Lith QTLs, including Lith1 – Lith23 . Therefore, using this knowledge, our priority is to predict human LITH genes. To date, predominantly, prior knowledge of gene-product function was invoked to postulate causal roles for genes in gallstone susceptibility. Unfortunately, few such genes colocalized with empirical Lith loci, suggesting absence of causality or very limited contributions. Consequently, we present a systematic and comprehensive analysis of literature to support or refute the contributions to gallstone susceptibility by genes located within critical regions of empirical QTLs. We envisage that identification of human LITH genes based on our translational approach will provide targets for the development of new means of prevention and nonsurgical management of cholelithiasis.