Gilbert’s syndrome: Molecular genetic markers

1. Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert’s syndrome? Atherosclerosis. 2015;239(1):73–84.

PMID: 25576848. https://doi.org/10.1016/j.atherosclerosis.2014.12.042

2. Bale G, Avanthi US, Padaki NR, Sharma M, Duvvur NR, Vishnubhotla VRK. Incidence and risk of gallstone disease in Gilbert’s syndrome patients in Indian population. J Clin Exp Hepatol. 2018;8(4):362–66.

PMID: 30563996. PMCID: PMC6286431. https://doi.org/10.1016/j.jceh.2017.12.006

3. Ruiz-Gaspa S, Guanabens N, Jurado S, Dubreuil M, Combalia A, Peris P et al. Bile acids and bilirubin effects on osteoblastic gene profile. Implications in the pathogenesis of osteoporosis in liver diseases. Gene. 2020;725:144167.

PMID: 31639434. https://doi.org/10.1016/j.gene.2019.144167

4. Jurado S, Parés A, Peris P, Combalia A, Monegal A, Guañabens N. Bilirubin increases viability and decreases osteoclast apoptosis contributing to osteoporosis in advanced liver diseases. Bone. 2022;162:116483.

PMID: 35787483. https://doi.org/10.1016/j.bone.2022.116483

5. Tcaciuc E, Podurean M, Tcaciuc A. Management of Crigler-Najjar syndrome. Med Pharm Rep. 2021;94(Suppl No 1):S64–S67.

PMID: 34527915. PMCID: PMC8411811. https://doi.org/10.15386/mpr-2234

6. Grant LM, Faust TW, Chandrasekar VT, John S. Gilbert Syndrome. 2023. In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing. 2024. PMID: 29262099.

7. Steventon G. Uridine diphosphate glucuronosyltransferase 1A1. Xenobiotica. 2020;50(1):64–76.

PMID: 31092094. https://doi.org/10.1080/00498254.2019.1617910

8. Horsfall LJ, Zeitlyn D, Tarekegn A, Bekele E, Thomas MG, Bradman N, Swallow DM. Prevalence of clinically relevant UGT1A alleles and haplotypes in African populations. Ann Hum Genet. 2011;75(2):236–46.

PMID: 21309756. https://doi.org/10.1111/j.1469-1809.2010.00638.x

9. Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol. 2013;19(38):6398–6407.

PMID: 24151358. PMCID: PMC3801310. https://doi.org/10.3748/wjg.v19.i38.6398

10. Innocenti F, Schilsky RL, Ramírez J, Janisch L, Undevia S, House LK et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol. 2014;32(22):2328–34.

PMID: 24958824. PMCID: PMC4105486. https://doi.org/10.1200/jco.2014.55.2307

11. Marin JJG, Serrano MA, Monte MJ, Sanchez-Martin A, Temprano AG, Briz O, Romero MR. Role of genetic variations in the hepatic handling of drugs. Int J Mol Sci. 2020;21(8):2884.

PMID: 32326111. PMCID: PMC7215464. https://doi.org/10.3390/ijms21082884

12. King D, Armstrong MJ. Overview of Gilbert’s syndrome. Drug Ther Bull. 2019;57(2):27–31.

PMID: 30709860. https://doi.org/10.1136/dtb.2018.000028

13. Bulmer AC, Bakrania B, Du Toit EF, Boon A-C, Clark PJ, Powell LW et al. Bilirubin acts as a multipotent guardian of cardiovascular integrity: More than just a radical idea. Am J Physiol Heart Circ Physiol. 2018;315(3):H429–H447.

PMID: 29600900. https://doi.org/10.1152/ajpheart.00417.2017

14. Gazzin S, Masutti F, Vitek L, Tiribelli C. The molecular basis of jaundice: An old symptom revisited. Liver Int. 2017;37(8):1094–1102.

PMID: 28004508. https://doi.org/10.1111/liv.13351

15. Jirasková A, Skrha J, Vítek L. Association of low serum bilirubin concentrations and promoter variations in the UGT1A1 and HMOX1 genes with type 2 diabetes mellitus in the Czech population. Int J Mol Sci. 2023;24(13):10614.

PMID: 37445792. PMCID: PMC10342136. https://doi.org/10.3390/ijms241310614

16. Inoguchi T, Nohara Y, Nojiri C, Nakashima N. Association of serum bilirubin levels with risk of cancer development and total death. Sci Rep. 2021;11(1):13224.

PMID: 34168201. PMCID: PMC8225648. https://doi.org/10.1038/s41598-021-92442-2

17. Ruiz-Gaspa S, Martinez-Ferrer A., Guañabens N, Dubreuil M, Peris P, Enjuanes A et al. Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases. Hepatology. 2011;54(6):2104–13.

PMID: 21837749. https://doi.org/10.1002/hep.24605

18. Lin R, Wang X, Wang Y, Zhang F, Wang Y, Fu W et al. Association of polymorphisms in four bilirubin metabolism genes with serum bilirubin in three Asian populations. Hum Mutat. 2009;30(4):609–15.

PMID: 19243019. https://doi.org/10.1002/humu.20895

19. UGT1A1. UDP glucuronosyltransferase family 1 member A1 (Homo sapiens (human)). URL: https://www.ncbi.nlm.nih.gov/gene/54658 (date of access – 31.03.2025).

20. Hsieh T-Y, Shiu T-Y, Huang S-M, Lin H-H, Lee T-C, Chen P-J et al. Molecular pathogenesis of Gilbert’s syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmacogenet Genomics. 2007;17(4):229–36.

PMID: 17496722. https://doi.org/10.1097/FPC.0b013e328012d0da

21. Vitek L, Tiribelli C. Bilirubin: The yellow hormone? J Hepatol. 2021;75(6):1485–90.

PMID: 34153399. https://doi.org/10.1016/j.jhep.2021.06.010

22. Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol. 2003;38(1):107–17.

PMID: 12480568. https://doi.org/10.1016/s0168-8278(02)00359-8

23. Li Z, Song L, Hao L. The role of UGT1A1 (c.-3279T>G) gene polymorphisms in neonatal hyperbilirubinemia susceptibility. BMC Med Genet. 2020;21(1):218.

PMID: 33158427. PMCID: PMC7648392. https://doi.org/10.1186/s12881-020-01155-2

24. Иванова А.А., Гуражева А.А., Мельникова Е.С., Максимов В.Н., Немцова Е.Г. Исследование молекулярно-генетических маркеров синдрома Жильбера. Бюллетень сибирской медицины. 2023;22(2):39–45. (Ivanova AA, Gurazheva AA, Mel’nikova ES, Maksimov VN, Nemtsova EG. Study of molecular genetic markers of Gilbert’s syndrome. Byulleten’ sibirskoy meditsiny = Bulletin of Siberian Medicine. 2023;22(2):39–45 (In Russ.)).

EDN: WAHYWU. https://doi.org/10.20538/1682-0363-2023-2-39-45

25. Волков А.Н. Популяционно-генетическое исследование мутации гена UGT1A1, ассоциированной со сниженной функцией печеночной УДФ-глюкуронилтрансферазы А1. Фундаментальная и клиническая медицина. 2020;5(3):59–65. (Volkov AN. Population genetic research of the mutation in UGT1A1 gene associated with reduced activity of liver UDP-glucuronosyltransferase A1. Fundamental’naya i klinicheskaya meditsina = Fundamental and Clinical Medicine. 2020;5(3):59–65 (In Russ.)).

EDN: PRQXNW. https://doi.org/10.23946/2500-0764-2020-5-3-59-65

26. Хомутов Е.В., Кишеня М.С., Кисс А.И., Иващенко Д.А., Гандак И.М. Молекулярно-генетическое тестирование синдрома Жильбера. Университетская клиника. 2024;(1):43–46. (Khomutov EV, Kishenya MS, Kiss AI, Ivashchenko DA, Gandak IM. Molecular genetic development of Gilbert’s syndrome. Universitetskaya klinika = University Clinic. 2024;(1):43–46 (In Russ.)). EDN: DVQOHR.

27. Шрайнер Е.В., Хавкин А.И., Новикова М.С., Кох Н.В., Денисов М.Ю., Лифшиц Г.И. Оценка вклада полиморфизмов гена UGT1A в развитие желчнокаменной болезни. Экспериментальная и клиническая гастроэнтерология. 2023;(10):133–138. (Shreiner EV, Khavkin AI, Novikova MS, Kokh NV, Denisov MYu, Lifshits GI. Assessment of the contribution of UGT1A gene polymorphisms to the development of cholelithiasis. Eksperimental’naya i klinicheskaya gastroenterologiya = Experimental and Clinical Gastroenterology. 2023;(10):133–138 (In Russ.)).

EDN: ATOSBU. https://doi.org/10.31146/1682-8658-ecg-218-10-133-138

28. Сидоренко Д.В., Назаров В.Д., Волникова Е.Г., Кондрашева Е.А., Пешкова Н.Г., Ковалева И.С. с соавт. Зависимость биохимических показателей крови от различных генотипов гена UGT1A1, ассоциированного с синдромом Жильбера. Клиническая лабораторная диагностика. 2022;67(2):69–75. (Sidorenko DV, Nazarov VD, Volnikova EG, Kondrasheva EA, Peshkova NG, Kovaleva IS et al. Dependence of blood biochemical parameters on various genotypes of the UGT1A1 gene associated with Gilbert’s syndrome. Klinicheskaya laboratornaya diagnostika = Clinical Laboratory Diagnostics. 2022;67(2):69–75 (In Russ.)).

EDN: VWQTEZ. https://doi.org/10.51620/0869-2084-2022-67-2-69-75

29. Chen Z, Su D, Ai L, Jiang X, Wu C, Xu Q et al. UGT1A1 sequence variants associated with risk of adult hyperbilirubinemia: A quantitative analysis. Gene. 2014;552(1):32–38.

PMID: 25200497. https://doi.org/10.1016/j.gene.2014.09.009

30. Zhou J, Yang C, Zhu W, Chen S, Zeng Y, Wang J et al. Identification of genetic risk factors for neonatal hyperbilirubinemia in Fujian province, Southeastern China: A case-control study. Biomed Res Int. 2018;2018:7803175.

PMID: 30298137. PMCID: PMC6157199. https://doi.org/10.1155/2018/7803175

31. Vukovic M, Radlovic N, Lekovic Z, Vucicevic K, Maric N, Kotur N et al. UGT1A1 (TA)n promoter genotype: Diagnostic and population pharmacogenetic marker in Serbia. Balkan J Med Genet. 2018;21(1):59–68.

PMID: 30425912. PMCID: PMC6231317. https://doi.org/10.2478/bjmg-2018-0012

32. Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR; Pediatrix Hyperbilirubinemia Study Group. Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatrics. 2009;124(5):e868–77.

PMID: 19858149. https://doi.org/10.1542/peds.2009-0460

33. Watchko JF, Lin Z. Genetics of neonatal jaundice. In: Stevenson DK, Maisels MJ, Watchko JF. Care of the jaundiced neonate. New York: McGraw-Hill Medical. 2012: 1–27. ISBN: 139780071762892.

34. Maruo Y, D’Addario C, Mori A, Iwai M, Takahashi H, Sato H, Takeuchi Y. Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome. Hum Genet. 2004;115(6):525–26.

PMID: 15378351. https://doi.org/10.1007/s00439-004-1183-x

35. Watchko JF. Genetics and pediatric unconjugated hyperbilirubinemia. J Pediatr. 2013;162(2):1092–94.

PMID: 23453772. https://doi.org/10.1016/j.jpeds.2013.01.044

36. Gu L, Han Y, Zhang D, Gong Q, Zhang X. Genetic testing of UGT1A1 in the diagnosis of Gilbert syndrome: The discovery of seven novel variants in the Chinese population. Mol Genet Genomic Med. 2022;10(7):e1958.

PMID: 35426266. PMCID: PMC9266601. https://doi.org/10.1002/mgg3.1958

37. Zhang M, Wang H, Huang Y, Xu X, Liu W, Ning Q et al. Compound heterozygous UGT1A1*28 and UGT1A1*6 or single homozygous UGT1A1*28 are major genotypes associated with Gilbert’s syndrome in Chinese Han people. Gene. 2021;781:145526.

PMID: 33631237. https://doi.org/10.1016/j.gene.2021.145526

38. Gailite L, Rots D, Pukite I, Cernevska G, Kreile M. Case report: Multiple UGT1A1 gene variants in a patient with Crigler – Najjar syndrome. BMC Pediatr. 2018;18(1):317.

PMID: 30285761. PMCID: PMC6169020. https://doi.org/10.1186/s12887-018-1285-6

39. Bai J, Luo L, Liu S, Liang C, Bai L, Chen Y et al. Combined Effects of UGT1A1 and SLCO1B1 variants on Chinese adult mild unconjugated hyperbilirubinemia. Front Genet. 2019;10:1073.

PMID: 31737051. PMCID: PMC6834774. https://doi.org/10.3389/fgene.2019.01073

40. Datta S, Chowdhury A, Ghosh M, Das K, Jha P, Colah R et al. A genome-wide search for non-UGT1A1 markers associated with unconjugated bilirubin level reveals significant association with a polymorphic marker near a gene of the nucleoporin family. Ann Hum Genet. 2012;76(1):33–41.

PMID: 22118420. https://doi.org/10.1111/j.1469-1809.2011.00688.x

41. Kringen MK, Piehler AP, Grimholt RM, Opdal MS, Haug KBF, Urdal P. Serum bilirubin concentration in healthy adult North-Europeans is strictly controlled by the UGT1A1 TA-repeat variants. PLoS One. 2014;9(2):e90248.

PMID: 24587300. PMCID: PMC3938665. https://doi.org/10.1371/journal.pone.0090248

42. Sikorska K, Romanowski T, Stalke P, Jaskiewicz K, Bielawski KP. Coexistence of HFE and rare UGT1A1 genes mutations in patients with iron overload related liver injury. Adv Med Sci. 2010;55(1):108–10.

PMID: 20371435. https://doi.org/10.2478/v10039-010-0003-x

43. Zhang L, Liu Z, Xue L. Rare case of primary Sjogren’s syndrome coexisting with Gilbert syndrome. Cureus. 2023;15(9):e45521.

PMID: 37868557. PMCID: PMC10585419. https://doi.org/10.7759/cureus.45521

44. Tiwari PK, Sethi A, Basu S, Raman R, Kumar A. Heme oxygenase-1 gene variants and hyperbilirubinemia risk in North Indian newborns. Eur J Pediatr. 2013;172(12):1627–32.

PMID: 23877636. https://doi.org/10.1007/s00431-013-2091-7

45. D’Silva S, Colah RB, Ghosh K, Mukherjee MB. Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates. Gene. 2014;547(1):18–22.

PMID: 24865931. https://doi.org/10.1016/j.gene.2014.05.047