Association of ABCG5 and ABCG8 Polymorphisms with Gallstone Disease and Gallbladder Cancer

Aim: to analyze the role of nucleotide sequence variants (NSVs) of ABCG5 and ABCG8 genes in gallstone disease (GSD) and gallbladder cancer (GBC).

Key points. ABCG5 and ABCG8 are key sterol efflux transporters that regulate hepatic secretion and intestinal absorption of cholesterol. ABCG5/G8 is the human LITH9 gallstone gene. One of the major genetic risk factors for GSD rs11887534 (D19H) ABCG8, as a ‘gain-of-function’ NSV, increases the activity of this transporter by 3.2 times, which leads to supersaturation of bile with cholesterol and an increased risk of GSD. On average, rs11887534 increases

the risk of GSD in children by 4 times, in adults — by 2 times, which has been proven in population, genome-wide studies and meta-analyses worldwide. The presence of the H allele D19H (rs11887534) is associated with a two-fold risk of recurrence of GSD after cholecystectomy. The results of the studies of the associations of GSD with other NSVs of ABCG8 (T400K, A632V, M429V, C54Y) and ABCG5 (E604Q, R50C) genes are contradictory.

In population studies, rs11887534 was associated with a 4-fold increase in the risk of GBC, and the risk is more prominent (4.9 times) in patients with GBC and gallstones. We found no studies of the NSVs of the ABCG5 and ABCG8 genes in biliary pathology in Russia.

Conclusion. Most studies confirm the role of the rs11887534 ABCG8 gene as a predictor of GSD and GBC; however, replicating studies of NSVs of ABCG5 and ABCG8 genes in biliary pathology in Russia are needed.

1. Moore J.M., Bell E.L., Hughes R.O., Garfield A.S. ABC transporters: Human disease and pharmacotherapeutic potential. Trends Mol Med. 2023;29(2):152–72. DOI:10.1016/j.molmed.2022.11.001

2. Wang H.H., Liu M., Portincasa P., Wang D.Q. Recent advances in the critical role of the sterol efflux transporters ABCG5/G8 in health and disease. Adv Exp Med Biol. 2020;1276:105–36.DOI:10.1007/978-981-15-6082-8_8

3. Patel S.B., Graf G.A., Temel R.E. ABCG5 and ABCG8: More than a defense against xenosterols. J Lipid Res. 2018;59(7):1103–13. DOI:10.1194/jlr.R084244

4. Stender S., Frikke-Schmidt R., Nordestgaard B.G., Tybjærg-Hansen A. The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease. J Am Coll Cardiol. 2014;63(20):2121–8. DOI: 10.1016/j.jacc.2013.12.055

5. Scholz M., Horn K., Pott J., Gross A., Kleber M.E., Delgado G.E., et al. Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis. Nat Commun. 2022;13(1):143. DOI:10.1038/s41467-021-27706-6

6. Teng M.S., Yeh K.H., Hsu L.A., Chou H.H., Er L.K., Wu S., et al. Differential effects of ABCG5/G8 gene region variants on lipid profile, blood pressure status, and gallstone disease history in Taiwan. Genes (Basel). 2023;14(3):754. DOI:10.3390/genes14030754

7. Zein A.A., Kaur R., Hussein T.O.K., Graf G.A., Lee J.Y. ABCG5/G8:A structural view to pathophysiology of the hepatobiliary cholesterol secretion. Biochem Soc Trans. 2019;47(5):1259–68.DOI:10.1042/BST20190130

8. Graf G.A., Cohen J.C., Hobbs H.H. Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking. J Biol Chem. 2004;279(23):24881–8. DOI:10.1074/jbc.M402634200

9. Yu L., Li-Hawkins J., Hammer R.E., Berge K.E., Horton J.D., Cohen J.C., et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002;110(5):671–80. DOI:10.1172/JCI16001

10. Grigor’eva I.N., Notova T.E. Apolipoprotein E gene polymorphism, gallstone disease, diabetes 2 type and lipid metabolism disorders. Ateroscleroz. 2023;19(1):479–88. (In Russ.)]. DOI: 10.52727/2078-256X-2023-19-1-479-488

11. Wang H.H., Li X., Patel S.B., Wang D.Q. Evidence that the adenosine triphosphate-binding cassette G5/G8-independent pathway plays a determinant role in cholesterol gallstone formation in mice. Hepatology. 2016;64(3):853–64. DOI:10.1002/hep.28570

12. Grigor’eva I.N., Ragino Yu.I., Romanova T.I., Malyutina S.K. Association between coronary heart disease and gallstone disease (epidemiological study). Ateroscleroz. 2019;15(2):32–8. (In Russ.)]. DOI: 10.15372/ATER20190205

13. Lebedeva M.S., Grigor’eva I.N., Tatarnikova N.P., Maksimov V.N. Some common candidate genes in arterial hypertension and gall stone disease pathogenesis. Ateroscleroz. 2014;10(2):43–50. (In Russ.)].

14. Grigor’eva I.N., Slobodchikova M.A., Maximov V.N., Denisova D.V., Zavayalova L.G. Polymorphism of the APOE gene and bile lithogenicity in the persons with positive familial history for gallstonedisease. Vestnik NSU. Series: Biology.2011;9(1):93–8. (In Russ.).

15. Grigor'eva I.N., Ragino Yu.I., Schakhtschneider E.V., Ryabikov A.N., Verevkin E.G., Voevoda M.I. Gallstone disease: Results of our 20-year studies (Part 1: epidemiology, lipids of blood serum and bile, apolipoprotein E polymorphism). Dnevnik Kazanskoy Meditsinskoy Shkoly. 2016;2(12):18–23. (In Russ.).

16. Buch S., Schafmayer C., Völzke H., Becker C., Franke A., von Eller-Eberstein H., et al . A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.Nat Genet.2007;39(8):995–9. DOI:10.1038/ng2101

17. Costa C.J., Nguyen M.T.T., Vaziri H., Wu G.Y. Gene tics of gallstone disease and their clinical significance: A narrative review. J Clin Transl Hepatol. 2024;12(3):316–26. DOI: 10.14218/JCTH.2023.00563

18. Sarin S.K., Negi V.S., Dewan R., Sasan S., Saraya A. High familial prevalence of gallstones in the first-degree relatives of gallstone patients. Hepatology. 1995;22(1):138–41.

19. Nakeeb A., Comuzzie A.G., Martin L., Sonnenberg G.E., Swartz-Basile D., Kissebah A.H., et al. Gallstones: Genetics versus environment. Ann Surg. 2002;235(6):842–9. DOI: 10.1097/00000658-200206000-00012

20. Katsika D., Grjibovski A., Einarsson C., Lammert F., Lichtenstein P., Marschall H.U. Genetic and environmental influences on symptomatic gall stone disease: A Swedish study of 43,141 twin pairs. Hepatology. 2005;41(5):1138–43. DOI: 10.1002/hep.20654

21. Kuo K.K., Shin S.J., Chen Z.C., Yang Y.H., Yang J.F., Hsiao P.J. Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gall stone disease. Br J Surg. 2008;95(8):1005–11. DOI: 10.1002/bjs.6178

22. Grünhage F., Acalovschi M., Tirziu S., Walier M., Wienker T.F., Ciocan A., et al. Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology. 2007;46(3):793–801. DOI:10.1002/hep.21847

23. Krawczyk M., Niewiadomska O., Jankowska I., Jankowski K., Więckowski S., Lebensztejn D., et al. Common variant p. D19H of the hepatobiliary sterol transporter ABCG8 increases the risk of gallstones in children. Liver Int. 2022;42(7):1585–92. DOI:10.1111/liv.15186

24. Katsika D., Magnusson P., Krawczyk M., Grünhage F., Lichtenstein P., Einarsson C., et al. Gallstone disease in Swedish twins: Risk is associated with ABCG8 D19H genotype. J Intern Med. 2010;268(3):279–85. DOI:10.1111/j.1365-2796.2010.02249.x

25. Wittenburg H., Lyons M.A., Li R., Kurtz U., Mössner J., Churchill G.A., et al. Association of a lithogenic Abcg5/Abcg8allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice. Mamm Genome. 2005;16(7):495–504. DOI:10.1007/s00335-005-0006-2

26. Stender S., Frikke-Schmidt R., Nordestgaard B.G., Tybjaerg-Hansen A. Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population. Hepatology. 2011;53(2):640–8. DOI: 10.1002/ hep.24046

27. Krawczyk M., Wang D.Q., Portincasa P., Lammert F. Dissecting the genetic heterogeneity of gallbladder stone formation. Semin Liver Dis. 2011;31(2):157–72. DOI:10.1055/s-0031-1276645

28. von Kampen O., Buch S., Nothnagel M., Azocar L., Molina H., Brosch M., et al. Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus. Hepatology. 2013;57(6):2407–17. DOI: 10.1002/hep.26009

29. von Schönfels W., Buch S., Wölk M., Aselmann H., Egberts J.H., Schreiber S., et al. Recurrence of gallstones after cholecystectomy is associated with ABCG5/8 genotype. J Gastroenterol. 2013;48(3):391–6. DOI: 10.1007/ s00535-012-0639-3

30. Berge K.E., von Bergmann K., Lutjohann D., Guerra R., Grundy S.M., Hobbs H.H., et al. Heritability of plasma non cholesterol sterol sand relationship to DNA sequence polymorphism in ABCG5 and ABCG8. J Lipid Res. 2002;43(3):486–94.

31. Jiang Z.Y., Parini P., Eggertsen G., Davis M.A., Hu H., Suo G.J., et al. Increased expression of LXR alpha, ABCG5, ABCG8, and SR-BI in the liver from normolipidemic, no nobese Chinese gallstone patients. J Lipid Res. 2008;49(2):464–72. DOI:10.1194/jlr.M700295-JLR200

32. Xu H.L., Cheng J.R., Andreotti G., Gao Y.T., Rashid A., Wang B.S., et al. Cholesterol metabolism gene polymorphisms and the risk of biliary tract cancers and stones: A population-based case-control study in Shanghai, China. Carcinogenesis. 2011;32(1):58–62. DOI: 10.1093/carcin/bgq194

33. Goodloe R., Brown-Gentry K., Gillani N.B., Jin H., Mayo P., Allen M., et al. Lipid trait-associated gene tic variation is associated with gallstone disease in thediverse Third National Health and Nutrition Examination Survey (NHANES III). BMC Med Genet. 2013;14:120. DOI:10.1186/1471-2350-14-120

34. Joshi A.D., Andersson C., Buch S., Stender S., Noordam R., Weng L.C., et al. Four susceptibility loci for gall stone disease identified in a meta-analysis of genome-wide association studies. Gastroenterology. 2016;151(2):351–63.e28. DOI:10.1053/j.gastro.2016.04.007

35. Bustos B.I., Pérez-Palma E., Buch S., Azócar L., Ri veras E., Ugarte G.D., et al. Variants in ABCG8 and TRAF3genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American an cestry. Sci Rep.2019;9(1):772.DOI:10.1038/s41598-018-35852-z

36. Srivastava A., Srivastava A., Srivastava K., Choudhuri G., Mittal B. Role of ABCG8 D19H (rs11887534) variant in gallstone susceptibility in northern India. J Gastroenterol Hepatol. 2010;25(11):1758–62. DOI: 10.1111/j.1440-1746.2010.06349.x

37. Siddapuram S.P., Mahurkar S., Duvvuru N.R., Mitnala S., Guduru V.R., Rebala P., et al. Hepatic cholesterol transporter ABCG8 polymorphisms in gallstone disease in an Indian population. J Gastroenterol Hepatol. 2010;25(6):1093–8. DOI: 10.1111/j.1440-1746.2010.06309.x

38. Liang K.W., Huang H.H., Wang L., Lu W.Y., Chou Y.H., Tantoh D.M., et al. Risk of gallstones based on ABCG8 rs11887534 single nucleotide polymorphism among Taiwanese men and women. BMC Gastroenterol. 2021;21(1):468. DOI: 10.1186/s12876-021-02060-5

39. Milanizadeh S., Mohebbi S.R., Khanyaghma M., Mohammad Alizadeh A.H. ATP binding cassette and cholecystokinin A receptor genetic variations in gallstone susceptibility. Gastroenterol Hepatol Bed Bench. 2017;10(Suppl 1):S108–16.

40. Rudkowska I., Jones P.J .PolymorphismsinABCG5/G8transporters linked to hypercholesterolemia and gallstone disease. Nutr Rev. 2008;66(6):343–8. DOI: 10.1111/j.1753-4887.2008.00042.x

41. Jiang Z.Y., Cai Q., Chen E.Z. Association of three common single nucleotide polymorphisms of ATP binding cassette G8 genewith gallstonedisease: A meta-analysis. PLoS One. 2014;9(1):e87200. DOI: 10.1371/journal.pone.0087200

42. Acalovschi M., Ciocan A., Mostean O., Tirziu S., Chiorean E., Keppeler H., et al. Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms? A preliminary study in siblings with gallstones. Eur J Intern Med. 2006;17(7):490–4. DOI: 10.1016/j.ejim.2006.04.012

43. Chauhan T., Mittal R.D., Mittal B.Association of common single nucleotide polymorphisms of candidate genes with gallstone disease: A meta-analysis. Indian J Clin Biochem.2020;35(3):290–311. DOI: 10.1007/s12291-019-00832-1

44. Wang Y., Jiang Z.Y., Fei J., Xin L., Cai Q., Jiang Z.H., et al.ATP binding cassette G8 T400K polymorphism may affect therisk of gallstonediseaseamong Chinese males. Clin Chim Acta. 2007;384(1–2):80–5. DOI: 10.1016/j.cca.2007.06.004

45. Grigor’eva I.N., Efimova O.V., Tov N.L., Suvorova T.S., Nepomnyashchikh D.L. Metabolic risk factors and their impact on quality of life in patients with pancreatic cancer, acute or exacerbated chronic pancreatitis. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2023;33(3):49–60. (In Russ.). DOI: 10.22416/1382-4376-2023-33-3-49-60

46. Pandey M. Risk factors for gallbladder cancer: A reappraisal. Eur J Cancer Prev. 2003;12(1):15–24. DOI: 10.1097/00008469-200302000-00004

47. García P., Lamarca A., Díaz J., Carrera E., Roa J.C. Current and new biomarkers for early detection, prognostic stratification, and management of gallbladder cancer patients. Cancers (Basel). 2020;12(12):3670. DOI: 10.3390/cancers12123670

48. Randi G., Franceschi S., La Vecchia C. Gall bladder cancer world wide: Geographical distribution and risk factors. Int J Cancer. 2006;118(7):1591–602.DOI:10.1002/ijc.21683

49. Andreotti G., Chen J., Gao Y.T., Rashid A., Chen B.E., Rosenberg P., et al. Polymorphisms of genes in the lipid metabolism pathway and risk of biliary tract cancers and stones: A population-based case-control study in Shanghai, China. Cancer Epidemiol Biomarkers Prev. 2008;17(3):525–34. DOI:10.1158/1055-9965.EPI-07-2704

50. Srivastava A., Tulsyan S., Pandey S.N., Choudhuri G., Mittal B. Single nucleotide polymorphism in the ABCG8 transporter gene is associated with gallbladder cancer susceptibility. Liver Int. 2009;29(6):831–7. DOI:10.1111/j.1478-3231.2008.01907.x

51. Mhatre S., Wang Z., Nagrani R., Badwe R., Chiplunkar S., Mittal B., et al. Common genetic variation and risk of gallbladder cancer in India: A case-control genome-wide association study. Lancet Oncol. 2017;18(4):535–54. DOI:10.1016/S1470-2045(17)30167-5

52. Boekstegers F, Marcelain K., Barahona Ponce C., Baez Benavides P.F., Müller B., de Toro G., et al .ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans. Cancer Epidemiol. 2020;65:101643. DOI: 10.1016/j.canep.2019.101643

53. Stättermayer A.F., Halilbasic E., Wrba F., Ferenci P., Trauner M. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol. 2020;73(3):651–63. DOI: 10.1016/j.jhep.2020.04.036