Association of ABCB4 and ABCB11 nucleotide variants with intrahepatic cholestasis of pregnancy

Milena Gruszczyńska-Losy; Adrianna Mostowska; Łukasz Adamczak; Paweł Jagodziński; Ewa Wender-Ożegowska; Małgorzata Kędzia

doi:10.20883/medical.388

Authors

Milena Gruszczyńska-Losy Gynecologic and Obstetrical University Hospital in Poznan, Poland https://orcid.org/0000-0003-2630-2026
Adrianna Mostowska Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0003-4181-9402
Łukasz Adamczak Division of Reproduction, Department of Obstetrics, Gynecology and Gynecological Oncology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-2511-1407
Paweł Jagodziński Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-9046-6802
Ewa Wender-Ożegowska Division of Reproduction, Department of Obstetrics, Gynecology and Gynecological Oncology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-5492-8651
Małgorzata Kędzia Division of Reproduction, Department of Obstetrics, Gynecology, and Gynecologic Oncology, Poznan University of Medical Sciences, Poznan, Poland https://orcid.org/0000-0002-8115-2019

DOI:

https://doi.org/10.20883/medical.388

Keywords:

Intrahepatic Cholestasis of Pregnancy, ABCB4, ABCB11, nucleotide variants

Abstract

Background. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during gestation. The exact pathogenesis of ICP is multifactorial and still unclear. Therefore, our study aimed to check whether the selected ABCB4and ABCB11nucleotide variants are associated with an increased risk of ICP.

Methods. ICP was diagnosed based on clinical symptoms characteristic of this disease and confirmed by increase in serum bile acids and transaminases, spontaneous resolution of clinical symptoms and normalization of laboratory tests after delivery. The total of 86 pregnant women meeting the criteria were included into the study. Healthy pregnant women with uncomplicated pregnancy served as control group (n=310). Sixcommon nucleotide variants in theABCB11and ABCB4genes were genotypedwith the use of high-resolution melting curve analysis.

Conclusions. Our study did not show any significant association of analysed ABCB4and ABCB11nucleotide variants with the increased risk of intrahepatic cholestasis of pregnancy.

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References

McIlvride S, Dixon PH, Williamson C. Bile acids and gestation. Mol Aspects Med. 2017 Aug; 56:90–100.

Yeap SP, Harley H, Thompson R, Williamson KD, Bate J, Sethna F, et al. Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications. J Gastroenterol Hepatol. 2019 Feb;34(2):425–435.

Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population‑based case‑control study. Hepatology. 2014 Apr;59(4):1482–1491.

Kawakita T, Parikh LI, Ramsey PS, Huang CC, Zeymo A, Fernandez M, et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol. 2015 Oct;213(4): 570.e1–8.

Eloranta ML, Heinonen S, Mononen T, Saarikoski S. Risk of obstetric cholestasis in sisters of index patients. Clin Genet. 2001 Jul;60(1):42–45.

Webb GJ, Elsharkawy AM, Hirschfield GM. The etiology of intrahepatic cholestasis of pregnancy: towards solving a monkey puzzle. Am J Gostroenterol. 2014 Jan;109(1):85–88.

Reyes H, Gonzalez MC, Ribalta J, Aburto H, Matus C, Schramm G, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med. 1978 Apr;88(4):487–493.

Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol. 2006 Sep;26(9):527–532.

van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):541–553.

Piątek K, Kurzawińska G, Magiełda J, Drews K, Barlik M, Malewski Z, et al. The role of ABC transporters' gene polymorphism in the etiology of intrahepatic cholestasis of pregnancy. Ginekol Pol. 2018;89(7):393–397.

Nicolaou M, Andress EJ, Zolnerciks JK, Dixon PH, Williamson C, Linton KJ. Canalicular ABC transporters and liver disease. J Pathol. 2012 Jan;226(2):300–315.

Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, et al. ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. Dig Liver Dis. 2013 Mar;45(3):226–232.

Wasmuth HE, Glantz A, Keppeler H, Simon E, Bartz C, Rath W, et al. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut. 2007 Feb;56(2):265–270.

Aamann L, Ørntoft N, Vogel I, Grønbaek H, Becher N, Vilstrup H, et al. Unexplained cholestasis in adults and adolescents: diagnostic benefit of genetic examination. Scand J Gastroenterol. 2018 Mar;53(3):305–311.

Reichert MC, Lammert F. ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum. Semin Liver Dis. 2018 Nov;38(4):299–307.

Pauli‑Magnus C, Lang T, Meier Y, Zodan‑Marin T, Jung D, Breymann C, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p‑glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Farmacogenetics. 2004 Feb;14(2):91–102.

Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, et al. Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations. Aliment Farmacol Ther. 2006 Jun;23(11):1649–1653.

Schneider G, Paus TC, Kullak‑Ublick GA, Meier PJ, Wienker TF, Lang T, et al. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology. 2007 Jan;45(1):150–158.

Eloranta ML, Häkli T, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy. Scand J Gastroenterol. 2003 Jun;38(6):648–652.

Painter JN, Savander M, Sistonen P, Lehesjoki AE, Aittomäki K. A known polymorphism in the bile salt export pump gene is not a risk allele for intrahepatic cholestasis of pregnancy. Scand J Gastroenterol. 2004 Jul;39(7):694–695.

Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut. 2009 Apr;58(4):537–544.

Dixon PH, Wadsworth CA, Chambers J, Donnelly J, Cooley S, Buckley R, et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol. 2014 Jan;109(1):76–84.

Müllenbach R, Weber SN, Krawczyk M, Zimmer V, Sarrazin C, Lammert F, et al. A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population. BMC Gastroenterol. 2012 Jun; 12:63.

Dixon PH, Sambrotta M, Chambers J, Taylor‑Harris P, Syngelaki A, Nicolaides K, et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep. 2017 Sep;7(1):11823.

Gonzalez MC, Reyes H, Arrese M, Figueroa D, Lorca B, Andresen M, et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol. 1989 Jul;9(1):84–90.

Eloranta ML, Heiskanen JT, Hiltunen MJ, Mannermaa AJ, Punnonen KR, Heinonen ST. Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis. Europ J Obstet Gynecol Reprod Biol. 2002 Nov;105(2):132–135.