The Impact of Five VDR Polymorphisms on Multiple Sclerosis Risk and Progression: a Case-Control and Genotype-Phenotype Study

  • Pavel Křenek
  • Yvonne Benešová
  • Julie Bienertová-Vašků
  • Anna Vašků
Article

Abstract

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, pa = 0.02; Taq, pg = 0.02, pa = 0.02; BsmI, pg = 0.02, pa = 0.04; ApaI, pg = 0.008, pa = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: pg = 0.01, pa = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT pcorr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women.

Keywords

Multiple sclerosis Single-nucleotide polymorphism Vitamin D receptor EDSS MSSS 

Notes

Acknowledgements

The authors would like to thank the laboratory personnel of the Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, and the employees of the Department of Neurology, University Hospital Brno, for their help. The authors would also like to thank all patients and controls for participating in the study.

Compliance with Ethical Standards

The study was approved by the Ethics Committee of University Hospital Brno and all procedures were performed in accordance with the Helsinki Declaration as revised in 2013. Written informed consent was obtained from all study participants.

Conflict of Interest

The authors declare that there is no conflict of interests.

References

  1. Abdollahzadeh R, Fard MS, Rahmani F, Moloudi K, Kalani BS, Azarnezhad A (2016) Predisposing role of vitamin D receptor (VDR) polymorphisms in the development of multiple sclerosis: a case-control study. J Neurol Sci 367:148–151.  https://doi.org/10.1016/j.jns.2016.05.053 CrossRefPubMedGoogle Scholar
  2. Agliardi C, Guerini FR, Saresella M, Caputo D, Leone MA, Zanzottera M, Bolognesi E, Marventano I, Barizzone N, Fasano ME, Al-Daghri N, Clerici M (2011) Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. Brain Behav Immun 25(7):1460–1467.  https://doi.org/10.1016/j.bbi.2011.05.015 CrossRefPubMedGoogle Scholar
  3. Agnello L, Scazzone C, Ragonese P, Salemi G, Lo Sasso B, Schillaci R, Musso G, Bellia C, Ciaccio M (2016) Vitamin D receptor polymorphisms and 25-hydroxyvitamin D in a group of Sicilian multiple sclerosis patients. Neurol Sci 37(2):261–267.  https://doi.org/10.1007/s10072-015-2401-0 CrossRefPubMedGoogle Scholar
  4. Al-Temaimi RA, Al-Enezi A, Al-Serri A, Alroughani R, Al-Mulla F (2015) The association of vitamin D receptor polymorphisms with multiple sclerosis in a case-control study from Kuwait. PLoS One 10(11):e0142265.  https://doi.org/10.1371/journal.pone.0142265 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Antico A, Tampoia M, Tozzoli R, Bizzaro N (2012) Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. Autoimmun Rev 12(2):127–136.  https://doi.org/10.1016/j.autrev.2012.07.007 CrossRefPubMedGoogle Scholar
  6. Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61(4):288–299CrossRefPubMedGoogle Scholar
  7. Ascherio A, Munger KL, Simon KC (2010) Vitamin D and multiple sclerosis. Lancet Neurol 9(6):599–612.  https://doi.org/10.1016/S1474-4422(10)70086-7 CrossRefPubMedGoogle Scholar
  8. Benešová Y, Vašků A, Štourač P, Hladíková M, Beránek M, Kadaňka Z, Novotná H, Bednařík J (2008) Matrix metalloproteinase-9 and matrix metalloproteinase-2 gene polymorphisms in multiple sclerosis. J Neuroimmunol 205(1–2):105–109CrossRefPubMedGoogle Scholar
  9. Benešová Y, Vašků A, Stourač P, Hladíková M, Fiala A, Bednařík J (2013a) Association of HLA-DRB1*1501 tagging rs3135388 gene polymorphism with multiple sclerosis. J Neuroimmunol 255(1–2):92–96.  https://doi.org/10.1016/j.jneuroim.2012.10.014 CrossRefPubMedGoogle Scholar
  10. Benešová Y, Vašků A, Štourač P, Hladíková M, Fiala A, Bednařík J (2013b) Association of HLA-DRB1*1501 tagging rs3135388 gene polymorphism with multiple sclerosis. J Neuroimmunol 255(1–2):92–96CrossRefPubMedGoogle Scholar
  11. Ben-Selma W, Ben-Fredj N, Chebel S, Frih-Ayed M, Aouni M, Boukadida J (2015) Age- and gender-specific effects on VDR gene polymorphisms and risk of the development of multiple sclerosis in Tunisians: a preliminary study. Int J Immunogenet 42(3):174–181.  https://doi.org/10.1111/iji.12197 CrossRefPubMedGoogle Scholar
  12. Čierny D, Michalik J, Kurča E, Dobrota D, Lehotský J (2015) FokI vitamin D receptor gene polymorphism in association with multiple sclerosis risk and disability progression in Slovaks. Neurol Res 37(4):301–308.  https://doi.org/10.1179/1743132814Y.0000000459 CrossRefPubMedGoogle Scholar
  13. Čierny D, Michalik J, Škereňová M, Kantorová E, Sivák Š, Javor J, Kurča E, Dobrota D, Lehotský J (2016) ApaI, BsmI and TaqI VDR gene polymorphisms in association with multiple sclerosis in Slovaks. Neurol Res 38(8):678–684.  https://doi.org/10.1080/01616412.2016.1200287 CrossRefPubMedGoogle Scholar
  14. Compston A, Coles A (2002) Multiple sclerosis. Lancet 359(9313):1221–1231CrossRefPubMedGoogle Scholar
  15. Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517.  https://doi.org/10.1016/S0140-6736(08)61620-7 CrossRefPubMedGoogle Scholar
  16. Cox MB, Ban M, Bowden NA, Baker A, Scott RJ, Lechner-Scott J (2012) Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis. Mult Scler 18(1):16–22.  https://doi.org/10.1177/1352458511415562 CrossRefPubMedGoogle Scholar
  17. D’Aurizio F, Villalta D, Metus P, Doretto P, Tozzoli R (2015) Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases? Autoimmun Rev 14(5):363–369.  https://doi.org/10.1016/j.autrev.2014.10.008 CrossRefPubMedGoogle Scholar
  18. Das UN (2005) Is angiotensin-II an endogenous pro-inflammatory molecule? Med Sci Monit 11:155–162Google Scholar
  19. Dickinson JL, Perera DI, van der Mei AF, Ponsonby AL, Polanowski AM, Thomson RJ, Taylor BV, McKay JD, Stankovich J, Dwyer T (2009) Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 vitamin D receptor variant in this interaction. Mult Scler 15(5):563–570.  https://doi.org/10.1177/1352458509102459 CrossRefPubMedGoogle Scholar
  20. Fukazawa T, Yabe I, Kikuchi S, Sasaki H, Hamada T, Miyasaka K, Tashiro K (1999) Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese. J Neurol Sci 166(1):47–52CrossRefPubMedGoogle Scholar
  21. García-Martín E, Agúndez JA, Martínez C, Benito-León J, Millán-Pascual J, Calleja P, Díaz-Sánchez M, Pisa D, Turpín-Fenoll L, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Plaza-Nieto JF, Jiménez-Jiménez FJ (2013) Vitamin D3 receptor (VDR) gene rs2228570 (Fok1) and rs731236 (Taq1) variants are not associated with the risk for multiple sclerosis: results of a new study and a meta-analysis. PLoS One 8(6):e65487.  https://doi.org/10.1371/journal.pone.0065487 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hladíková M, Vašků A, Štourač P, Benešová Y, Bednařík J (2011) Two frequent polymorphisms of angiotensinogen and their association with multiple sclerosis progression rate. J Neurol Sci 303(1–2):31–34CrossRefPubMedGoogle Scholar
  23. Huang J, Xie ZF (2012) Polymorphisms in the vitamin D receptor gene and multiple sclerosis risk: a meta-analysis of case-control studies. J Neurol Sci 313(1–2):79–85.  https://doi.org/10.1016/j.jns.2011.09.024 CrossRefPubMedGoogle Scholar
  24. International Multiple Sclerosis Genetics Consortium (IMSGC), Wellcome Trust Case Control Consortium 2 (WTCCC2); International IBD Genetics Consortium (IIBDGC), Beecham AH et al (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45:1353–1360CrossRefGoogle Scholar
  25. International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219CrossRefGoogle Scholar
  26. Jadidi-Niaragh F, Mirshafiey A (2011) Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74:1–13CrossRefPubMedGoogle Scholar
  27. Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C (2001) Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol 50(4):434–442CrossRefPubMedGoogle Scholar
  28. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 33:1444–1452CrossRefPubMedGoogle Scholar
  29. Leppert D, Ford J, Stabler G, Grygar C, Lienert C, Huber S et al (1998) Matrix metalloproteinase −9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 121:2327–2334CrossRefPubMedGoogle Scholar
  30. Mamutse G, Woolmore J, Pye E, Partridge J, Boggild M, Young C, Fryer A, Hoban PR, Rukin N, Alldersea J, Strange RC, Hawkins CP (2008) Vitamin D receptor gene polymorphism is associated with reduced disability in multiple sclerosis. Mult Scler 14(9):1280–1283.  https://doi.org/10.1177/1352458508094643 CrossRefPubMedGoogle Scholar
  31. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127CrossRefPubMedGoogle Scholar
  32. Milo R, Kahana E (2010) Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev 9(5):A387–A394.  https://doi.org/10.1016/j.autrev.2009.11.010 CrossRefPubMedGoogle Scholar
  33. Munger KL, Hongell K, Åivo J, Soilu-Hänninen M, Surcel HM, Ascherio A (2017) 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. Neurology 89(15):1578–1583.  https://doi.org/10.1212/WNL.0000000000004489 CrossRefPubMedGoogle Scholar
  34. Murray ED, Buttner EA, Price BH (2012) Depression and psychosis in neurological practice. In: Daroff R, Fenichel G, Jankovic J, Mazziotta J (eds) Bradley’s neurology in clinical practice, 6th edn. Elsevier Saunders, Philadelphia, pp 103–116Google Scholar
  35. Narooie-Nejad M, Moossavi M, Torkamanzehi A, Moghtaderi A, Salimi S (2015a) Vitamin D receptor gene polymorphism and the risk of multiple sclerosis in South Eastern of Iran. J Mol Neurosci 56(3):572–576.  https://doi.org/10.1007/s12031-015-0513-x CrossRefPubMedGoogle Scholar
  36. Narooie-Nejad M, Moossavi M, Torkamanzehi A, Moghtaderi A (2015b) Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population. Biomed Res Int 2015:427519.  https://doi.org/10.1155/2015/427519 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Newman TA, Woolley ST, Hughes PM, Sibson NR, Anthony DC, Perry VH (2001) T-cell- and macrophage mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases. Brain 124:2203–2214CrossRefPubMedGoogle Scholar
  38. Niino M, Fukazawa T, Yabe I, Kikuchi S, Sasaki H, Tashiro K (2000) Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles. J Neurol Sci 177(1):65–71CrossRefPubMedGoogle Scholar
  39. Partridge JM, Weatherby SJ, Woolmore JA, Highland DJ, Fryer AA, Mann CL, Boggild MD, Ollier WE, Strange RC, Hawkins CP (2004) Susceptibility and outcome in MS: associations with polymorphisms in pigmentation-related genes. Neurology 62(12):2323–2325CrossRefPubMedGoogle Scholar
  40. Pittock SJ, Lucchinetti CF (2007) The pathology of MS: new insights and potential clinical applications. Neurologist 13:45–56CrossRefPubMedGoogle Scholar
  41. Ram M, Sherer Y, Shoenfeld Y (2006) Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol 26:299–307CrossRefPubMedGoogle Scholar
  42. Rhead B, Bäärnhielm M, Gianfrancesco M, Mok A, Shao X, Quach H, Shen L, Schaefer C, Link J, Gyllenberg A, Hedström AK, Olsson T, Hillert J, Kockum I, Glymour MM, Alfredsson L, Barcellos LF (2016) Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet 2(5):e97.  https://doi.org/10.1212/NXG.0000000000000097 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, SØrensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sá M, Salemi G, Savettieri G, Hillert J, Compston DA (2005) Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 64:1144–1151CrossRefPubMedGoogle Scholar
  44. Sadovnick AD (2012) Genetic background of multiple sclerosis. Autoimmun Rev 11:163–166CrossRefPubMedGoogle Scholar
  45. Schmied MC, Zehetmayer S, Reindl M, Ehling R, Bajer-Kornek B, Leutmezer F, Zebenholzer K, Hotzy C, Lichtner P, Meitinger T, Wichmann HE, Illig T, Gieger C, Huber K, Khalil M, Fuchs S, Schmidt H, Auff E, Kristoferitsch W, Fazekas F, Berger T, Vass K, Zimprich A (2012) Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients. Neurogenetics 13:181–187CrossRefPubMedGoogle Scholar
  46. Simon KC, Munger KL, Yang X, Ascherio A (2010) Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Mult Scler 16(2):133–138.  https://doi.org/10.1177/1352458509355069 CrossRefPubMedGoogle Scholar
  47. Sioka C, Papakonstantinou S, Markoula S, Gkartziou F, Georgiou A, Georgiou I, Pelidou SH, Kyritsis AP, Fotopoulos A (2011) Vitamin D receptor gene polymorphisms in multiple sclerosis patients in northwest Greece. J Negat Results Biomed 10:3.  https://doi.org/10.1186/1477-5751-10-3 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Smolders J, Damoiseaux J, Menheere P, Tervaert JW, Hupperts R (2009a) Fok-I vitamin D receptor gene polymorphism (rs10735810) and vitamin D metabolism in multiple sclerosis. J Neuroimmunol 207(1–2):117–121.  https://doi.org/10.1016/j.jneuroim.2008.12.011 CrossRefPubMedGoogle Scholar
  49. Smolders J, Damoiseaux J, Menheere P, Tervaert JW, Hupperts R (2009b) Association study on two vitamin D receptor gene polymorphisms and vitamin D metabolites in multiple sclerosis. Ann N Y Acad Sci 1173:515–520.  https://doi.org/10.1111/j.1749-6632.2009.04656.x CrossRefPubMedGoogle Scholar
  50. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J (2003) Inflammation and angiotensin II. Int J Biochem Cell Biol 35:881–900CrossRefPubMedGoogle Scholar
  51. Tajouri L, Ovcaric M, Curtain R, Johnson MP, Griffiths LR, Csurhes P, Pender MP, Lea RA (2005) Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet 19(1):25–38CrossRefPubMedGoogle Scholar
  52. Tizaoui K, Kaabachi W, Hamzaoui A, Hamzaoui K (2015) Association between vitamin D receptor polymorphisms and multiple sclerosis: systematic review and meta-analysis of case-control studies. Cell Mol Immunol 12(2):243–252.  https://doi.org/10.1038/cmi.2014.47 CrossRefPubMedGoogle Scholar
  53. Yamout B, Karaky NM, Mahfouz RA, Jaber F, Estaitieh N, Shamaa D, Abbas F, Hoteit R, Daher RT (2016) Vitamin D receptor biochemical and genetic profiling and HLA-class II genotyping among Lebanese with multiple sclerosis—a pilot study. J Neuroimmunol 293:59–64.  https://doi.org/10.1016/j.jneuroim.2016.02.008 CrossRefPubMedGoogle Scholar
  54. Yang CY, Leung PS, Adamopoulos IE, Gershwin ME (2013) The implication of vitamin D and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol 45(2):217–226.  https://doi.org/10.1007/s12016-013-8361-3 CrossRefPubMedGoogle Scholar
  55. Yushchenko M, Mader M, Elitok E, Bitsch A, Dressel A, Tumani H, Bogumil T, Kitze B, Poser S, Weber F (2003) Interferon-beta-1b decreased matrixmetalloproteinase-9 serum levels in primary progressive multiple sclerosis. J Neurol 250:1224–1228CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Pavel Křenek
    • 1
  • Yvonne Benešová
    • 2
  • Julie Bienertová-Vašků
    • 1
  • Anna Vašků
    • 1
  1. 1.Department of Pathological Physiology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  2. 2.Department of Neurology, University Hospital Brno and Faculty of MedicineMasaryk UniversityBrnoCzech Republic

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