Vol 91, No 12 (2020)
Research paper
Published online: 2020-12-31

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FokI vitamin D receptor polymorphism as a protective factor in intrahepatic cholestasis of pregnancy

Hubert Wolski12, Grazyna Kurzawinska13, Marcin Ozarowski4, Krzysztof Drews1, Magdalena Barlik1, Krzysztof Piatek1, Zbyszko Malewski1, Aleksandra E. Mrozikiewicz5, Justyna Magielda-Stola1, Dorota Kolanowska1, Marlena Wolek6, Agnieszka Seremak-Mrozikiewicz137
Pubmed: 33447990
Ginekol Pol 2020;91(12):719-725.


Objectives: Intrahepatic cholestasis in pregnancy (ICP) is a pregnancy-specific liver disorder. Its etiology is not fully understood. Increasing evidence indicates the important role of vitamin D and the vitamin D receptor (VDR) in this disorder. The presence of polymorphic variants in the VDR gene could influence its activity and susceptibility to ICP development. The goal of the study was to investigate the role of four genetic polymorphisms of the VDR gene — Fok (rs731236), Bsm (rs1544410), Apa (rs7975232), and Taq (rs731236) — in the etiology of ICP in Polish women. Material and methods: Ninety-eight women with confirmed ICP and 215 healthy pregnant women as a control group were recruited to the study. We examined four SNPs of the VDR gene: BsmI (rs7975232), TaqI (rs1544410), ApaI (rs228570), FokI (rs731236). Genotyping was performed using the PCR/RFLP method. Results: We observed higher frequency (borderline significant) of the Ff-ff genotypes containing at least one mutated allele of the VDR FokI polymorphism in the control group compared to the ICP group (p = 0.045, OR = 1.71, 95% CI 1.01–2.88). The frequency of the mutated f allele was slightly higher in controls (49.1%) than in the ICP group (43.4%) (OR = 1.26, 95% CI 0.90–1.77), but the difference was not statistically significant (p = 0.196). Conclusions: Our results showed that the maternal VDR FokI polymorphism could play a protective role in ICP development and probably modulate the risk of ICP occurrence in pregnant women in the Polish population. In the future, to confirm these observations, research in larger, ethnically stratified and clinically analyzed groups is necessary.

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  1. Bacq Y, Sentilhes L. Intrahepatic cholestasis of pregnancy: Diagnosis and management. Clin Liver Dis (Hoboken). 2014; 4(3): 58–61.
  2. Smith DD, Rood KM. Intrahepatic Cholestasis of Pregnancy. Clin Obstet Gynecol. 2020; 63(1): 134–151.
  3. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2009; 15(17): 2049–2066.
  4. Nakagawa K, Kawaura A, Kato S, et al. 1 alpha,25-Dihydroxyvitamin D(3) is a preventive factor in the metastasis of lung cancer. Carcinogenesis. 2005; 26(2): 429–440.
  5. Bouillon R, Eelen G, Verlinden L, et al. Vitamin D and cancer. J Steroid Biochem Mol Biol. 2006; 102(1-5): 156–162.
  6. Wang J, Wang Y, Han H, et al. Association of Vitamin D Receptor Gene Polymorphisms with Metabolic Syndrome in Rural Areas of China. Biomed Environ Sci. 2019; 32(4): 304–308.
  7. Pike JW, Meyer MB, Lee SM, et al. The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest. 2017; 127(4): 1146–1154.
  8. Wikström Shemer E, Marschall HU. Decreased 1,25-dihydroxy vitamin D levels in women with intrahepatic cholestasis of pregnancy. Acta Obstet Gynecol Scand. 2010; 89(11): 1420–1423.
  9. Gençosmanoğlu Türkmen G, Vural Yilmaz Z, Dağlar K, et al. Low serum vitamin D level is associated with intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res. 2018; 44(9): 1712–1718.
  10. Dror DK. Vitamin D status during pregnancy: maternal, fetal, and postnatal outcomes. Curr Opin Obstet Gynecol. 2011; 23(6): 422–426.
  11. Gilani S, Janssen P. Maternal Vitamin D Levels During Pregnancy and Their Effects on Maternal-Fetal Outcomes: A Systematic Review. J Obstet Gynaecol Can. 2020; 42(9): 1129–1137.
  12. Lapillonne A. Vitamin D deficiency during pregnancy may impair maternal and fetal outcomes. Med Hypotheses. 2010; 74(1): 71–75.
  13. Rizzo G, Garzon S, Fichera M, et al. Vitamin D and Gestational Diabetes Mellitus: Is There a Link? Antioxidants (Basel). 2019; 8(11).
  14. Gallo S, McDermid JM, Al-Nimr RI, et al. Vitamin D Supplementation during Pregnancy: An Evidence Analysis Center Systematic Review and Meta-Analysis. J Acad Nutr Diet. 2020; 120(5): 898–924.e4.
  15. Fogacci S, Fogacci F, Banach M, et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Vitamin D supplementation and incident preeclampsia: A systematic review and meta-analysis of randomized clinical trials. Clin Nutr. 2020; 39(6): 1742–1752.
  16. Jefferson KK, Parikh HI, Garcia EM, et al. Relationship between vitamin D status and the vaginal microbiome during pregnancy. J Perinatol. 2019; 39(6): 824–836.
  17. Evans KN, Bulmer JN, Kilby MD, et al. Vitamin D and placental-decidual function. J Soc Gynecol Investig. 2004; 11(5): 263–271.
  18. Ganguly A, Tamblyn JA, Finn-Sell S, et al. Vitamin D, the placenta and early pregnancy: effects on trophoblast function. J Endocrinol. 2018; 236(2): R93–R9R103.
  19. Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006; 147(12): 5542–5548.
  20. Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008; 88(2): 491S–499S.
  21. Fan L, Tu X, Zhu Y, et al. Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. J Gastroenterol Hepatol. 2005; 20(2): 249–255.
  22. Haussler MR, Whitfield GK, Kaneko I, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013; 92(2): 77–98.
  23. Harris SS, Eccleshall TR, Gross C, et al. The VDR start codon polymorphism (Fok-I) and bone mineral density in premenopausal American Black and White women. J Bone Miner Res. 1997; 12: 1043–1048.
  24. Morrison NA, Qi JC, Tokita A, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994; 367(6460): 284–287.
  25. Pani MA, Knapp M, Donner H, et al. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes. 2000; 49(3): 504–507.
  26. R Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2019. https://www.R-project.org/ (12.05.2020).
  27. González JR, Armengol L, Solé X, et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007; 23(5): 644–645.
  28. Solé X, Guinó E, Valls J, et al. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006; 22(15): 1928–1929.
  29. Jones D, Donaldson P. Genetic factors in the pathogenesis of primary biliary cirrhosis. Clin Liver Dis. 2003; 7(4): 841–864.
  30. Fang F, Wang J, Pan J, et al. Relationship between vitamin D (1,25-dihydroxyvitamin D3) receptor gene polymorphisms and primary biliary cirrhosis risk: a meta-analysis. Genet Mol Res. 2015; 14(1): 981–988.
  31. Li Yj, Tang Yw, Shi Yq, et al. Polymorphisms in the vitamin D receptor gene and risk of primary biliary cirrhosis: a meta-analysis. J Gastroenterol Hepatol. 2014; 29(4): 706–715.
  32. Tanaka A, Nezu S, Uegaki S, et al. Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations. J Hepatol. 2009; 50(6): 1202–1209.
  33. Mo C, Lu Yu, Deng Y, et al. Lack of association between vitamin D receptor gene ApaI, BsmI, and TaqI polymorphisms and primary biliary cirrhosis risk: a meta-analysis. Tumour Biol. 2014; 35(5): 4913–4920.
  34. Thakkinstian A, D'Este C, Attia J. Haplotype analysis of VDR gene polymorphisms: a meta-analysis. Osteoporos Int. 2004; 15(9): 729–734.
  35. Floreani A, Gervasi M. New Insights on Intrahepatic Cholestasis of Pregnancy. Clin Liver Dis. 2016; 20(1): 177–189.
  36. Keitel V, Dröge C, Häussinger D. Targeting FXR in Cholestasis. Handb Exp Pharmacol. 2019; 256: 299–324.
  37. Brady CW. Liver Disease in Pregnancy: What's New. Hepatol Commun. 2020; 4(2): 145–156.
  38. Sticova E, Jirsa M. ABCB4 disease: Many faces of one gene deficiency. Ann Hepatol. 2020; 19(2): 126–133.