Dissecting the genetic heterogeneity of gallbladder stone formation

Gallstone disease affects almost 20% of individuals in Westernized countries. As its incidence in the developing countries is rising considerably, currently, it is the second most common gastroenterological condition worldwide. Gallstone formation is driven by an interaction between genetic and environmental risk factors. Previous studies have demonstrated that the genetic background accounts for ~25% of the total disease risk. Linkage and case-control studies of candidate genes and recent genome-wide studies have identified multiple lithogenic genes, in particular the hepatocanalicular cholesterol transporter ABCG5/G8 and the bilirubin conjugating enzyme UGT1A1, as major genetic determinants of gallstones in humans. In this review, we summarize the recent findings related to the genetics of cholelithiasis, update the inventory of human lithogenic genes, and relate the genetic studies to the pathobiologic background of the disease. In closing, future applications of genetic testing for gallstone carriers and asymptomatic family members are addressed.