Susceptibility to cholesterol gallstone formation: evidence that LITH genes also encode immune-related factors

Cholesterol gallstones are solid calculi that form in the gallbladder from bile constituents and chiefly comprise cholesterol. Cholesterol gallstones are prevalent and costly for healthcare systems. In addition to various environmental factors, genetic risk contributes substantially to gallstone susceptibility. Candidate gene approaches to identify contributory genes are based on prior knowledge of gene-protein function. Whether selected from the entire genome or from limited genomic regions detected by experimental linkage analyses, thus far, candidate genes predominantly were related to lipid homeostasis. Alternatively, comprehensive review of available data suggests that a fundamental driving force underlying cholesterol gallstone formation is inflammation. Therefore, we predict that Lith genes in mice and LITH genes in humans also encode inflammatory molecules, their receptors and other mediators. Indeed, many Lith loci, defined experimentally using inbred mouse models, co-localise with genes that encode inflammation-related proteins. Systematic review of the literature reveals evidence consistent with inflammatory responses that may dictate each of the three cornerstones of cholesterol gallstone formation: biliary cholesterol supersaturation; cholesterol nucleation; gallbladder hypomotility. Genetically targeted inbred mice represent a powerful tool to interrogate the relationship between immune-related genes and gallstone susceptibility. We urge researchers to consider inflammation-related genes when designing population case-control genetic association studies pertaining to the genetic basis of gallstones. Immune and inflammatory events underlie each criterion necessary for cholesterol gallstone formation, which suggests that variation within the respective genes is fundamental for gallstone formation. In turn, inflammatory mediators may exert a spectrum of effects in response to genetic variation within lipid homeostatic genes.