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Maternal–fetal vitamin D receptor polymorphisms significantly associated with preterm birth

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Preterm birth (PTB) is a complex trait with strong genetic background, whose etiology is not fully understood. It was recently suggested that pregnancy duration is affected by fetal genetic variation even more than by the maternal genome. Vitamin D receptor (VDR) is involved in embryonic implantation and fertility. We studied the association between both maternal and neonatal vitamin D receptor (VDR) genetic variation and PTB.

Methods

Maternal and fetal (umbilical cord) DNA was isolated from Jewish Israeli idiopathic preterm newborns (24–36 weeks, n = 146) and control term newborns (>37 weeks, n = 229). Maternal and fetal VDR polymorphisms (FokI, ApaI, BsmI, TaqI) were analyzed by restriction fragment length polymorphism analysis. Using SPSS analysis to correlate VDR genotypes with phenotypic variation: pregnancy duration, preterm birth and spontaneous miscarriages, adjusted for gravidity, parity and gender of newborn.

Results

Women homozygous to VDR ApaI (AA) genotype had significant twofold increase risk for PTB [OR 1.973, (CI) 1.183–3.289, p = 0.009] compared to heterozygous women. Male newborns had significant (p < 0.05) 1.73-fold increase of PTB. Women with history of previous (≥1) spontaneous miscarriage had a significant increased risk for PTB if their newborn carried either of the VDR BsmI homozygous (BB or bb) genotypes compared to the heterozygous (Bb) genotype [OR 6.857, (CI) 1.273–36.934, p = 0.018 and OR 9.231, (CI) 1.753–48.618, p = 0.008, respectively], or VDR ApaI homozygous (AA or aa) genotype compared to heterozygous (Aa) genotype [OR 4.33, (CI) 1.029–18.257, p = 0.046 and OR 7.2, (CI) 1.34–38.917, p = 0.021, respectively].

Conclusions

We show association between maternal and fetal VDR genotype variants with PTB.

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References

  1. Goldenberg RL, Culhane JF, Iams JD, Romero R (2008) Epidemiology and causes of preterm birth. Lancet Lond Engl 371:75–84. doi:10.1016/S0140-6736(08)60074-4

    Article  Google Scholar 

  2. York TP, Eaves LJ, Neale MC, Strauss JF (2014) The contribution of genetic and environmental factors to the duration of pregnancy. Am J Obstet Gynecol 210:398–405. doi:10.1016/j.ajog.2013.10.001

    Article  PubMed  Google Scholar 

  3. Crider KS, Whitehead N, Buus RM (2005) Genetic variation associated with preterm birth: review. Genet Med Off J Am Coll Med Genet 7:593–604. doi:10.109701.gim.0000187223.69947.db

  4. Grisaru-Granovsky S, Tevet A, Bar-Shavit R, Salah Z, Elstein D, Samueloff A, Altarescu G (2007) Association study of protease activated receptor 1 gene polymorphisms and adverse pregnancy outcomes: results of a pilot study in Israel. Am J Med Genet A 143A:2557–2563. doi:10.1002/ajmg.a.31985

    Article  CAS  PubMed  Google Scholar 

  5. Siddesh A, Parveen F, Misra MK, Phadke SR, Agrawal S (2014) Platelet-specific collagen receptor glycoprotein VI gene variants affect recurrent pregnancy loss. Fertil Steril 102(1078–1084):e3. doi:10.1016/j.fertnstert.2014.07.002

    Google Scholar 

  6. Rai V (2014) Methylenetetrahydrofolate reductase gene A1298C polymorphism and susceptibility to recurrent pregnancy loss: a meta-analysis. Cell Mol Biol Noisy Gd Fr 60:27–34 (PMID: 24970119)

    CAS  Google Scholar 

  7. Alkhuriji AF, Alhimaidi AR, Babay ZA, Wary AS (2013) The relationship between cytokine gene polymorphism and unexplained recurrent spontaneous abortion in Saudi females. Saudi Med J 34:484–489 (PMID: 23677264)

    PubMed  Google Scholar 

  8. Christakos S, DeLuca HF (2011) Minireview: vitamin D: is there a role in extraskeletal health? Endocrinology 152:2930–2936. doi:10.1210/en.2011-0243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N, Swaminathan R, Cooper C, Godfrey K (2010) SWS Study Group Low maternal vitamin D status and fetal bone development: cohort study. J Bone Miner Res Off J Am Soc Bone Miner Res 25:14–19. doi:10.1359/jbmr.090701

    Article  CAS  Google Scholar 

  10. Liu NQ, Hewison M (2012) Vitamin D, the placenta and pregnancy. Arch Biochem Biophys 523:37–47. doi:10.1359/jbmr.090701

    Article  CAS  PubMed  Google Scholar 

  11. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM (2013) Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ 346:f1169 (PMID: 23533188)

    Article  PubMed  Google Scholar 

  12. Barrera D, Avila E, Hernández G, Méndez I, González L, Halhali A, Larrea F, Morales A, Díaz L (2008) Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts. Reprod Biol Endocrinol 6:3. doi:10.1186/1477-7827-6-3

    Article  PubMed  PubMed Central  Google Scholar 

  13. Salamonsen LA, Nie G, Findlay JK (2002) Newly identified endometrial genes of importance for implantation. J Reprod Immunol 53:215–225 (PMID: 11730918)

    Article  CAS  PubMed  Google Scholar 

  14. Evans KN, Bulmer JN, Kilby MD, Hewison M (2004) Vitamin D and placental-decidual function. J Soc Gynecol Investig 11:263–271. doi:10.1016/j.jsgi.2004.02.002

    Article  CAS  PubMed  Google Scholar 

  15. Viganò P, Mangioni S, Pompei F, Chiodo I (2003) Maternal-conceptus cross talk—a review. Placenta 24(Suppl B):S56–S61 (PMID: 14559031)

  16. Piccinni MP, Scaletti C, Maggi E, Romagnani S (2000) Role of hormone-controlled Th1- and Th2-type cytokines in successful pregnancy. J Neuroimmunol 109:30–33 (PMID: 10969178)

    Article  CAS  PubMed  Google Scholar 

  17. Qin L-L, Lu F-G, Yang S-H, Xu H-L, Luo B-A (2016) Does maternal vitamin D deficiency increase the risk of preterm birth: a meta-analysis of observational studies. Nutrients 20:8. doi:10.3390/nu8050301

    Google Scholar 

  18. Fischer-Suárez N, Fernández-Alonso AM, Herrera-Muñoz A, Chedraui P, Pérez-López FR (2016) Maternal serum 25-hydroxyvitamin D and C-reactive protein levels in pregnancies complicated with threatened preterm labour. Gynecol Endocrinol 32:777–781. doi:10.1080/09513590.2016.1177011

    Article  PubMed  Google Scholar 

  19. Santoro D, Gagliostro G, Alibrandi A, Ientile R, Bellinghieri G, Savica V, Buemi M, Caccamo D (2014) Vitamin D receptor gene polymorphism and left ventricular hypertrophy in chronic kidney disease. Nutrients 6:1029–1037. doi:10.3390/nu6031029

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kanan RM (2013) The effect of FokI vitamin D receptor polymorphism on bone mineral density in Jordanian perimenopausal women. Indian J Hum Genet 19:233–238. doi:10.4103/0971-6866.116125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rojano-Mejía D, Coral-Vázquez RM, Coronel A, Cortes-Espinosa L, del Carmen Aguirre-García M, Valencia-Villalvazo EY, Canto P (2014) Relation of the estrogen receptor and vitamin D receptor polymorphisms with bone mineral density in postmenopausal Mexican-mestizo women. Gene 537:10–14. doi:10.1016/j.gene.2013.12.054

    Article  PubMed  Google Scholar 

  22. Shan J, Dai N, Yang XQ, Qian CY, Yang ZZ, Jin F, Li M, Wang D (2014) FokI polymorphism in vitamin D receptor gene and risk of breast cancer among Caucasian women. Tumour Biol 35:3503–3508. doi:10.1007/s13277-013-1462-z

    Article  CAS  PubMed  Google Scholar 

  23. Zhu B, Zhao HL, Ou C, Huang LS, Li PZ, Lao M (2014) Association of vitamin D receptor BsmI gene polymorphism with the risk of type 2 diabetes mellitus. J Recept Signal Transduct Res 34:458–462. doi:10.3109/10799893.2014.919592

    Article  CAS  PubMed  Google Scholar 

  24. Vasilopoulos Y, Sarafidou T, Kotsa K, Papadimitriou M, Goutzelas Y, Stamatis C, Bagiatis V, Tsekmekidou X, Yovos JG, Mamuris Z (2013) VDR TaqI is associated with obesity in the Greek population. Gene 512:237–239. doi:10.1016/j.gene.2012.10.044

    Article  CAS  PubMed  Google Scholar 

  25. Aslani S, Hossein-Nezhad A, Mirzaei K, Maghbooli Z, Afshar AN, Karimi F (2011) VDR FokI polymorphism and its potential role in the pathogenesis of gestational diabetes mellitus and its complications. Gynecol Endocrinol 27:1055–1060. doi:10.3109/09513590.2011.569786

    Article  CAS  PubMed  Google Scholar 

  26. Fang X, Li H, Diao Y, Shan R, Dong J, Li H, Ma Q, Hou Y, Kong B (2010) Cui J (2010) Polymorphisms in the MTHRF, VDR, MMP-9 and IL-β genes and the risk of premature rupture of membranes. Gynecol Obstet Invest 70:206–214. doi:10.1159/000318867

    Article  CAS  PubMed  Google Scholar 

  27. Valdivielso JM, Fernandez E (2006) Vitamin D receptor polymorphisms and diseases. Clin Chim Acta Int J Clin Chem 371:1–12. doi:10.1016/j.cca.2006.02.016

    Article  CAS  Google Scholar 

  28. Bodnar LM, Catov JM, Zmuda JM, Cooper ME, Parrott MS, Roberts JM, Marazita ML, Simhan HN (2010) Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for-gestational age births in white women. J Nutr 140:999–1006. doi:10.3945/jn.109.119636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Uitterlinden AG, Fang Y, Van Meurs JBJ, Pols HAP, Van Leeuwen JPTM (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338:143–156. doi:10.1016/j.gene.2004.05.014

    Article  CAS  PubMed  Google Scholar 

  30. Nasiri H, Forouzandeh M, Rasaee MJ, Rahbarizadeh F (2005) Modified salting-out method: high-yield, high-quality genomic DNA extraction from whole blood using laundry detergent. J Clin Lab Anal 19:229–232. doi:10.1016/j.gene.2004.05.014

    Article  CAS  PubMed  Google Scholar 

  31. Mizutani S, Wright J, Kobayashi H (2011) A new approach regarding the treatment of preeclampsia and preterm labor. Life Sci 88:17–23. doi:10.1016/j.lfs.2010.10.013

    Article  CAS  PubMed  Google Scholar 

  32. Swingle HM, Colaizy TT, Zimmerman MB, Morriss FH (2009) Abortion and the risk of subsequent preterm birth: a systematic review with meta-analyses. J Reprod Med 54:95–108 (PMID: 19301572)

    PubMed  Google Scholar 

  33. McElrath TF, Hecht JL, Dammann O, Boggess K, Onderdonk A, Markenson G, Harper M, Delpapa E, Allred EN, Leviton A (2008) Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification. Am J Epidemiol 168:980–989. doi:10.1093/aje/kwn202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Carless MA, Kraska T, Lintell N, Neale RE, Green AC, Griffiths LR (2008) Polymorphisms of the VDR gene are associated with presence of solar keratoses on the skin. Br J Dermatol 159:804–810. doi:10.1111/j.1365-2133.2008.08745.x

    Article  CAS  PubMed  Google Scholar 

  35. Joos L, Weir TD, Connett JE, Anthonisen NR, Woods R, Paré PD, Sandford AJ (2003) Polymorphisms in the beta2 adrenergic receptor and bronchodilator response, bronchial hyperresponsiveness, and rate of decline in lung function in smokers. Thorax 58:703–707 (PMCID: PMC1746784)

  36. Taboulet J, Frenkian M, Frendo JL, Feingold N, Jullienne A, de Vernejoul MC (1998) Calcitonin receptor polymorphism is associated with a decreased fracture risk in post-menopausal women. Hum Mol Genet 7:2129–2133 (PMID: 9817931)

    Article  CAS  PubMed  Google Scholar 

  37. Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 96:412–418. doi:10.1161/01.RES.0000157171.04054.30

    Article  CAS  PubMed  Google Scholar 

  38. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287. doi:10.1038/367284a0

    Article  CAS  PubMed  Google Scholar 

  39. Marco MP, Martínez I, Amoedo ML, Borràs M, Saracho R, Almirall J, Fibla J, Fernández E (1999) Vitamin D receptor genotype influences parathyroid hormone and calcitriol levels in predialysis patients. Kidney Int 56:1349–1353. doi:10.1038/367284a0

    Article  CAS  PubMed  Google Scholar 

  40. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S (1997) 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 277:1827–1830 (PMID: 9295274)

    Article  CAS  PubMed  Google Scholar 

  41. Rezende VB, Sandrim VC, Palei AC, Machado L, Cavalli RC, Duarte G, Tanus-Santos JE (2012) Vitamin D receptor polymorphisms in hypertensive disorders of pregnancy. Mol Biol Rep 39:10903–10906. doi:10.1007/s11033-012-1988-y

    Article  CAS  PubMed  Google Scholar 

  42. Morley R, Carlin JB, Pasco JA, Wark JD, Ponsonby A-L (2009) Maternal 25-hydroxyvitamin D concentration and offspring birth size: effect modification by infant VDR genotype. Eur J Clin Nutr 63:802–804. doi:10.1038/ejcn.2008.55

    Article  CAS  PubMed  Google Scholar 

  43. Thota C, Menon R, Fortunato SJ, Brou L, Lee JE, Al-Hendy A (2014) 1,25-Dihydroxyvitamin D deficiency is associated with preterm birth in African American and Caucasian women. Reprod. Sci. Thousand Oaks Calif 21:244–250. doi:10.1177/1933719113493513

    Article  CAS  Google Scholar 

  44. Weinert LS, Silveiro SP (2015) Maternal–fetal impact of vitamin D deficiency: a critical review. Matern Child Health J 19:94–101. doi:10.1007/s10995-014-1499-7

    Article  PubMed  Google Scholar 

  45. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM (2007) Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab 92:3517–3522. doi:10.1210/jc.2007-0718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. August P, Marcaccio B, Gertner JM, Druzin ML, Resnick LM, Laragh JH (1992) Abnormal 1,25-dihydroxyvitamin D metabolism in preeclampsia. Am J Obstet Gynecol 166:1295–1299 (PMID: 1566788)

    Article  CAS  PubMed  Google Scholar 

  47. Novakovic B, Sibson M, Ng HK, Manuelpillai U, Rakyan V, Down T, Beck S, Fournier T, Evain-Brion D, Dimitriadis E, Craig JM, Morley R, Saffery R (2009) Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface. J Biol Chem 284:14838–14848. doi:10.1074/jbc.M809542200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu PT, Stenger S, LiH Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C et al (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773. doi:10.1126/science.1123933

    Article  CAS  PubMed  Google Scholar 

  49. Esplin MS, Manuck TA, Varner MW, Christensen B, Biggio J, Bukowski R, Parry S, Zhang H, Huang H, Andrews W et al (2015) Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms. Am J Obstet Gynecol 213:429.e1–429.e9. doi:10.1016/j.ajog.2015.06.011

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Acknowledgements

This work was partially funded by the Israeli Ministry of Health grant.

Author contributions

TR: protocol/project development, data collection or management, data analysis, manuscript writing/editing. HS: manuscript writing/editing. GA: protocol/project development, manuscript writing/editing. SGG: protocol/project development, manuscript writing/editing. AT: data collection or management. RB: protocol/project development, data analysis, manuscript writing/editing.

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Authors and Affiliations

  1. Department of Nutrition, School of Health Sciences, Ariel University, Ariel, Israel

    Talya Rosenfeld, Hagit Salem & Ruth Birk

  2. Genetics Unit and Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel

    Talya Rosenfeld, Gheona Altarescu, Sorina Grisaru-Granovsky & Aharon Tevet

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  1. Talya Rosenfeld
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  2. Hagit Salem
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Correspondence to Ruth Birk.

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Funding

This study was partially funded by the Israeli ministry of health grant (Grant 11064).

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The authors declare no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Rosenfeld, T., Salem, H., Altarescu, G. et al. Maternal–fetal vitamin D receptor polymorphisms significantly associated with preterm birth. Arch Gynecol Obstet 296, 215–222 (2017). https://doi.org/10.1007/s00404-017-4412-y

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  • DOI: https://doi.org/10.1007/s00404-017-4412-y

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