Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

Abstract

Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.

Keywords: ABCG8 protein; ATP-binding cassette transporters; Cholelithiasis; Gallstones; Human; UDP-glucuronosyltransferase A1.

Fig. 1. Protein products of genes linked to GS disease and their functions in physiology and pathophysiology.

(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.

Fig. 2. Recommended approach for diagnosing genetically linked GSs, including a suggested algorithmic approach to identify patients at an increased risk for genetically associated GSs and diagnostic workup.

ABC, ATP-binding cassette; APO, apolipoprotein. The figure was created using BioRender.com.