UGT1A1 gene mutation as a marker indicating there is a high risk of Gilbert's syndrome: Theoretical and applied aspects

View or download the full article: 

A.N. Volkov1,2, E.V. Tsurkan2


1Kemerovo State Medical University, 22A Voroshilova Str., Kemerovo, 650056, Russian Federation
2Kemerovo Regional Clinical Hospital, 22 Oktyabr'skii Avenue, Kemerovo, 650000, Russian Federation


Gilbert's syndrome is a widely spread multi-factor pathology which is to a great extent genetically determined. Its basic etiological factor is lower activity of a liver enzyme, UDP-glucuronosyltransferase A1, caused by mutations in UGT1A1 gene. Functional disorders in the liver cause dyspepsia and concurrent acute and chronic diseases in the digestive system. The research goal was to substantiate the necessity and possibility to conduct mass examinations of population with molecular and genetic analysis of UGT1A1 gene in order to reveal Gilbert's syndrome. The authors performed molecular and genetic examination of UGT1A1 gene rs8175347 marker in 132 people living in Kemerovo region (population sampling) as well as in 71 patients who were supposed to have Gilbert's syndrome (clinical sampling).

Frequency of 28/28 mutant genotype of UGT1A1 gene associated with Gilbert's syndrome amounted to 13.6 % in the population sampling and it is quite consistent with previously published data. Therefore, a considerable rate of population includes people with potential or already revealed Gilbert's syndrome. Age structure of patients in the clinical group with 28/28 genotype revealed there was a wide spread of an age at which the diseases was first detected due to its apparent manifestation; age varied from 4 to 71 years with its modal value being equal to 15 years. Basing on the obtained data, it is suggested to implement mass examinations aimed at revealing Gilbert's syndrome at its prenosological stage; such examinations can be based on molecular-genetic technologies. When children aged 7-10 are comprehensively examined, they can also undergo genetic diagnostics aimed at revealing any mutations in UGT1A1 gene. Obtained genetic data can be taken into account by medical personnel with relevant medical specializations when they determine strategies aimed at preventing and curing Gilbert's syndrome.

Gilbert's syndrome, UDP-glucuronosyltransferase А1, UGT1A1, rs8175347, mutations in a gene, genotype, molecular and genetic examination, genetic diagnostics
Volkov A.N., Tsurkan E.V. UGT1A1 gene mutation as a marker indicating there is a high risk of Gilbert's syndrome: theoretical and applied aspects. Health Risk Analysis, 2019, no. 2, pp. 123–129. DOI: 10.21668/health.risk/2019.2.14.eng
  1. Strassburg C.P. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syn-drome). Best Practice & Research Clinical Gastroenterology, 2010, vol. 24, pp. 555–571.
  2. Memon N. Inherited disorders of bilirubin clearance. Pediatr Research, 2016, vol. 79, no. 3, pp. 378–386.
  3. Zakharova I., Pykov M., Kaloeva Z., Kataeva L., Shishkina S., Berezhnaya I. [et al.]. Gilberts syndrome in children: contemporary diagnostic potentialities. Pediatricheskaya farmakologiya, 2011, vol. 8, no. 4, pp. 101–104 (in Russian).
  4. Dubrovina G.M., Botvin'ev O.K., Kolotilina A.I. Combination of Gilbert's syndrome and gastrointestinal diseases. Russian Journal of Gastroenterology, Hepatology, Coloproctology, 2014, no. 3, pp. 13–21 (in Russian).
  5. Buch S., Schafmayer C., Völzke H., Seeger M., Miquel J.F., Sookoian S.C. [et al.]. Loci from a genome-wide analyses of bilirubin levels are associated with gallstone risk and composition. Gastroenterology, 2010, vol. 139, no. 6, pp. 1942–1951.
  6. Tsezou A., Tzetis M., Giannatou E., Spanos I., Roma E., Fretzayas A. [et al.]. Gilbert syndrome as a predisposing factor for cholelithiasis risk in the Greek adult population. Genet. Test. Mol. Biomarkers, 2009, vol. 13, no. 1, pp. 143–146.
  7. Carpenter S.L., Lieff S., Howard T.A., Eggleston B., Ware R.E. UGT1A1 promoter polymorphisms and the develop-ment of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia. American Journal of Hematology, 2008, vol. 83, no. 10, pp. 800–803.
  8. Chaouch L., Talbi E., Moumni I., Chaabene A.B., Kalai M., Chaouachi D. [et al.]. Early complication in sickle cell anemia children due to A(TA)nTAA polymorphism at the promoter of UGT1A1 gene. Disease Markers, 2013, vol. 35, no. 2, pp. 67–72.
  9. Matsui K., Maruo Y., Sato H., Takeuchi Y. Combined effect of regulatory polymorphisms on transcription of UGT1A1 as a cause of Gilbert syndrome. BMC Gastroenterology, 2010, vol. 10, no. 57. DOI: 10.1186/1471-230X-10-57
  10. Premawardhena A., Fisher C.A., Liu Y.T., Verma I.C., De Silva S., Arambepola M. [et al.]. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary im-plications. Blood Cells, Molecules and Diseases, 2003, vol. 31, pp. 98–101.
  11. Johnson A.D., Kavousi M., Smith A.V., Chen M.H., Dehghan A., Aspelund T. [et al.]. Genome-wide association meta-analysis for total serum bilirubin levels. Human Molecular Genetics, 2009, vol. 18, no. 14, pp. 2700–2710.
  12. Kang T., Kim H., Ju H., Kim J., Jeon Y., Lee H. [et al.]. Genome-wide association of serum bilirubin levels in Korean population. Human Molecular Genetics, 2010, vol. 19, no. 18, pp. 3672–3678.
  13. Hong A.L., Huo D., Kim H.J., Niu Q., Fackenthal D.L., Cummings S.A. [et al.]. UDP-Glucuronosyltransferase 1A1 gene polymorphisms and total bilirubin levels in an ethnically diverse cohort of women. Drug Metabolism & Disposition, 2007, vol. 35, no. 8, pp. 1254–1261.
  14. Timoshkina N.N., Bogomolova O.A., Zhuzhelenko I.A., Kabanov S.N., Kalabanova E.A., Mitashok I.S. [et al.]. Study of polymorphisms of UGT1A1 and DPYD genes in chemotherapy for colorectal cancer. Siberian Journal of Oncology, 2018, vol. 17, no. 6, pp. 49–56 (in Russian).
  15. Shatalova E.G., Loginov V.I., Braga E.A., Kazubskaia T.P., Sudomoina M.A., Blanchard R.L., Favorova O.O. As-sociation of polymorphisms in SULT1A1 and UGT1A1 genes with breast cancer risk and phenotypes in Russian women. Mol. Biol., 2006, vol. 40, no. 2, pp. 228–234.
  16. Marinkovic N., Pasalic D., Grskovic B., Ferencak G., Honović L., Rukavina A.S. Genotype frequencies of UDP-Glucuronosyltransferase 1A1 promoter gene polymorphism in the population of healthy Croatian pre-scholars. Collegium An-tropologicum, 2008, vol. 32, no. 3, pp. 725–729.
  17. Biondi M.L., Turri O., Dilillo D., Stival G., Guagnellini E. Contribution of the TATA-box genotype (Gilbert syn-drome) to serum bilirubin concentrations in the Italian population. Clinical Chemistry, 1999, vol. 45, no. 6, pp. 897–898.
  18. Te Morsche R.H., Zusterzeel P.L., Raijmakers M.T., Roes E.M., Steegers E.A., Peters W.H. Polymorphism in the promoter region of the bilirubin UDP-glucuronosyltransferase (Gilbert's syndrome) in healthy Dutch subjects. Hepatology, 2001, vol. 33, no. 3, pp. 765.
  19. Salazara J.M.F., Sevilla Á.R., Del Río Conde E., Bastús M.B. Distribución del genotipo A(TA)7TAA asociado al síndrome de Gilbert en la población española. Med. Clin. (Barcelona), 2000, vol. 115, pp. 540–541.
  20. Girard H., Butler L.M., Villeneuve L., Millikan R.C., Sinha R., Sandler R.S., Guillemette C. UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African Americans. Mutation Research, 2008, vol. 644, no. 1–2, pp. 56–63.
  21. Botvinyev O.K., Dubrovina G.M., Kolotilina A.I. Pathology of different portions of the gastrointestinal tract in children with Gilbert’s syndrome. Ros. Vestn. Perinatol. Pediat., 2015, no. 3, pp. 104–107 (in Russian).
  22. Volkov A.N., Khabieva S.M., Smirnova E.Yu. The genetic diagnostics of mutations UGT1A1 in practice of modern medicine. Russian Clinical Laboratory Diagnostics, 2018, vol. 63, no. 3, pp. 186–192.

You are here