Genetics of gallstone disease and their clinical significance
image: (A) ABC transporters: The normal functioning of ABCG8/ABCG5, ABCB4, and ABCB11 enables the transport of cholesterol, bile acids, and lipids into bile (left). Mutations in any of these result in increased cholesterol and lipids, while decreasing bile acids in bile, thus precipitating stone formation (right). (B) APO: Apolipoproteins function to stabilize cholesterol-containing vesicles (left). Mutations in apolipoproteins result in less effective binding to their receptors and increased serum cholesterol (right). (C) UGT1A1: uridine 5′-diphospho-glucuronosyltransferase 1A1 conjugates bilirubin through glucuronidation, thereby increasing its solubility in aqueous bile (left). Pathologic mutations result in reduced conjugated bilirubin in bile, leading to an increase in stone formation (right). (D) CFTR: Cystic fibrosis transmembrane conductance regulator facilitates the transport of chloride ions across various cell membranes along with water (left). Mutated CFTR reduces the transport of chloride ions, leading to decreased water content and predisposing to stone formation (right). (E) Mucin mutations: MUC1 and MUC2, transmembrane mucins, regulate the secretion of mucins such as MUC3 and MUC5B (left). Mutations in MUC1 and MUC2, resulting in decreased expression, lead to increased intraluminal mucins (MUC3, MUC5A, MUC5B), precipitating GS formation (right). ABC, ATP-binding cassette; APO, apolipoproteins; UGT1A1, uridine 5′-diphospho-glucuronosyltransferase 1A1; CFTR, cystic fibrosis transmembrane conductance regulator. The figure was created using BioRender.com.
Credit: Christopher J. Costa
Gallstone disease is a common condition, affecting approximately 10-20% of the global adult population. Of these, about 20% develop symptomatic disease, leading to significant healthcare utilization. The formation of gallstones is a multifactorial process, influenced by both genetic and environmental factors. Advances in genetic analysis have identified specific genetic variants that contribute to the development of gallstone disease, providing new insights into its pathogenesis and potential avenues for personalized treatment.
Gallstones can be categorized into cholesterol and bilirubin stones, with cholesterol stones accounting for about 90% of cases. The remaining 10% are primarily composed of bilirubin. The formation of gallstones occurs when bile components precipitate due to decreased solubility.
Cholesterol gallstones result from bile that is supersaturated with cholesterol, which is absorbed from the diet and synthesized de novo in the liver. Cholesterol is transported in the body by apolipoproteins, with ApoB100 and ApoE being particularly significant. Variants in the genes coding for these proteins can increase the risk of gallstone formation by reducing the efficiency of cholesterol clearance from the body. Additionally, ATP-binding cassette (ABC) transporters such as ABCG8 and ABCG5 play a crucial role in cholesterol excretion. Mutations in these genes can elevate cholesterol levels in bile, enhancing its lithogenicity and leading to gallstone formation.
Studies have identified specific genetic variants associated with an increased risk of cholesterol gallstones. For instance, mutations in ABCG8, such as the D19H variant, have been linked to a higher risk of gallstone disease in various populations, including Europeans and Mapuche Indians. Research in Asian populations has also highlighted this variant's association with increased gallstone incidence, particularly among women. These findings underscore the importance of genetic predisposition in gallstone formation and suggest potential targets for genetic screening and intervention.
Bilirubin gallstones are often linked to genetic defects affecting the conjugation and transport of bilirubin. Key genes involved in this process include UGT1A1, ABCC2, and CFTR. Pathogenic variants in these genes can lead to reduced bilirubin solubility and increased stone formation. For example, mutations in UGT1A1 can cause Gilbert's syndrome, characterized by mild unconjugated hyperbilirubinemia, which can predispose individuals to bilirubin gallstones. Similarly, defects in ABCC2, responsible for transporting conjugated bilirubin into bile, can lead to Dubin-Johnson syndrome, associated with a higher risk of bilirubin stone formation.
Recognizing genetic predispositions to gallstone disease has significant clinical implications. Genetic testing can aid in the diagnosis and management of patients at risk for gallstone disease, allowing for personalized treatment strategies. For instance, individuals with known genetic variants predisposing them to cholesterol gallstones might benefit from dietary modifications and medications that reduce bile cholesterol levels. Genetic counseling can also provide valuable information for affected individuals and their families, guiding decision-making regarding preventive measures and treatment options.
Gallstone disease involves complex interactions between genetic and environmental factors. Advances in genetic research have highlighted specific variants contributing to the formation of both cholesterol and bilirubin gallstones. Understanding these genetic influences is essential for improving the diagnosis, treatment, and prevention of gallstone disease. Further research is needed to elucidate the full spectrum of genetic factors involved and to develop targeted interventions that can reduce the burden of this common condition.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2023-00563
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
Follow us on X: @xiahepublishing
Follow us on LinkedIn: Xia & He Publishing Inc.