Cholelithiasis: genetic hypothesis

Abstract

In inbred mice gallstone susceptibility is determined by Lith (lithogenic) genes which promote cholesterol hypersecretion in bile as a response to a high-fat diet. At least three major classes of proteins can be considered as candidate genes: (a) enzymes involved in cholesterol metabolism regulation; (b) trans-membrane carrier proteins from hepatocyte into bile; (c) cytosolic transfer proteins which regulate intrahepatocyte trafficking. The main candidates are: Spgp, a transmembrane protein which produces bile salt transport. Its gene map in Lith 1 region (Chromosome 2) and its expression is increased in susceptible inbred strains of mice (C57L) of inbred mice. Cmoat is a carrier protein that promotes the secretion of conjugated substances in bile. Its gene map in Lith 2 region (Chromosome 19) and its expression is increased in susceptible inbred strains of mice fed on a lithogenic diet. HGMR is the enzyme that regulates de novo synthesis of cholesterol in the liver. Its activity increases in resistant strains fed on a lithogenic diet and unvaries in susceptible strains. Its gene does not reside in any Lith region, but one Lith gene could be responsible for its activity regulation. To date, the hypothesis of a genetic basis of cholelithiasis in men has only been investigated in one study, in which the association of cholelithiasis and a mutation in the C7AH gene was documented in a group of Mexican patients.