{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T02:24:27Z","timestamp":1781490267730,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Rijeka","award":["17.07.2.1.04"],"award-info":[{"award-number":["17.07.2.1.04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preterm birth (PTB) forms a heterogeneous group with possible genetic predisposition. 25(OH)-vitamin D3 plays a significant role during implantation, placentation, and the maintenance of normal pregnancy. The aim of our research was to examine whether FokI, Cdx2, and ApaI VDR gene variants, as well as serum concentrations of 25-hydroxy25(OH)-vitamin D3 in women and their newborns, might be predisposing factors for idiopathic spontaneous preterm birth. The patient group consisted of 44 pairs of women with ISPTB and their children, and the control group consisted of 44 pairs of women who delivered at term and their children. At the time of delivery, peripheral blood was collected from every woman, and after newborn delivery, umbilical cord blood was collected. For genotyping of the rs2228570 C\/T, rs11568820 G\/A, and rs7975232 T\/G SNPs, a combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was used. Serum concentrations of 25(OH)-vitamin D3 were determined using high-performance liquid chromatography (HPLC). There were no statistically significant differences in the frequencies of VDR genotypes and alleles between women with ISPTB and control women. There was a statistically significant difference in the distribution of VDR Cdx-2 (rs11568820) genotypes between preterm-born children and controls, with the GG genotype and G allele being more prevalent among patients than controls (p &lt; 0.001). There were no statistically significant differences in mean values between women with ISPTB and control women, nor between preterm and full-term newborns, although the 25(OH)-vitamin D3 concentrations in preterm-born children were lower than in controls. Furthermore, there was a statistically significant correlation in 25(OH)-vitamin D3 concentrations between mothers and children both in the patient and in the control groups (b = 0.771, p &lt; 0.001). The results of our study demonstrate a notable association between the VDR Cdx2 gene polymorphism and idiopathic spontaneous preterm birth (ISPTB) in a Caucasian population, but because of the small number of participants, further research is needed.<\/jats:p>","DOI":"10.3390\/ijms252111712","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T06:55:37Z","timestamp":1730357737000},"page":"11712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Association of 25(OH)-Vitamin D3 Serum Concentrations and Vitamin D Receptor Gene Variants with the Risk of Idiopathic Spontaneous Preterm Birth in the Croatian Population"],"prefix":"10.3390","volume":"25","author":[{"given":"Milena","family":"Ga\u0161parovi\u0107 Krpina","sequence":"first","affiliation":[{"name":"Croatia Policlinics, Vukovarska Ulica 7A, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8440-1722","authenticated-orcid":false,"given":"Sanja","family":"Devi\u0107 Pavli\u0107","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Bra\u0107e Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-9411","authenticated-orcid":false,"given":"Tea","family":"Mladeni\u0107","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Bra\u0107e Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4749-4760","authenticated-orcid":false,"given":"Merica","family":"Aralica","sequence":"additional","affiliation":[{"name":"Clinical Department of Laboratory Diagnostics, Clinical Hospital Center Rijeka, Vjekoslava Duki\u0107a 7, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Bari\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Clinics for Gynecology and Obstetrics, Clinical Hospital Center Rijeka, Vjekoslava Duki\u0107a 7, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1620-1865","authenticated-orcid":false,"given":"Alemka","family":"Brn\u010di\u0107-Fischer","sequence":"additional","affiliation":[{"name":"Clinics for Gynecology and Obstetrics, Clinical Hospital Center Rijeka, Vjekoslava Duki\u0107a 7, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7134-4335","authenticated-orcid":false,"given":"Sa\u0161a","family":"Ostoji\u0107","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Bra\u0107e Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Pereza","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Bra\u0107e Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bpobgyn.2018.04.003","article-title":"The global epidemiology of preterm birth","volume":"52","author":"Vogel","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1080\/00016340802005126","article-title":"Spontaneous preterm birth, a clinical dilemma: Etiologic, pathophysiologic and genetic heterogeneities and racial disparity","volume":"87","author":"Menon","year":"2008","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(08)60074-4","article-title":"Epidemiology and causes of preterm birth","volume":"371","author":"Goldenberg","year":"2008","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1203\/PDR.0b013e31818912e7","article-title":"Genetic contributions to disparities in preterm birth","volume":"65","author":"Anum","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1097\/01.gim.0000187223.69947.db","article-title":"Genetic variation associated with preterm birth: A HuGE review","volume":"7","author":"Crider","year":"2005","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1097\/GRF.0000000000000037","article-title":"Overview of spontaneous preterm birth: A complex and multifactorial phenotype","volume":"57","author":"Esplin","year":"2014","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0029-7844(97)00215-9","article-title":"The risk of preterm birth across generations","volume":"90","author":"Porter","year":"1997","journal-title":"Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1080S","DOI":"10.1093\/ajcn\/87.4.1080S","article-title":"Vitamin D deficiency: A worldwide problem with health consequences","volume":"87","author":"Holick","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, H., Wang, S., Tuo, L., Zhai, Q., Cui, J., Chen, D., and Xu, D. (2022). Relationship between Maternal Vitamin D Levels and Adverse Outcomes. Nutrients, 14.","DOI":"10.3390\/nu14204230"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s00774-011-0264-x","article-title":"High prevalence of hypovitaminosis D in pregnant Japanese women with threatened premature delivery","volume":"29","author":"Shibata","year":"2011","journal-title":"Bone Miner. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s00223-012-9607-4","article-title":"Vitamin D and pregnancy: Skeletal effects, nonskeletal effects, and birth outcomes","volume":"92","author":"Hollis","year":"2013","journal-title":"Calcif. Tissue Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jsbmb.2016.02.008","article-title":"Vitamin D supplementation during pregnancy: Updated meta-analysis on maternal outcomes","volume":"164","author":"Palacios","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Amegah, A.K., Klevor, M.K., and Wagner, C.L. (2017). Maternal vitamin D insufficiency and risk of adverse pregnancy and birth outcomes: A systematic review and meta-analysis of longitudinal studies. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173605"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.mayocp.2013.05.011","article-title":"Vitamin D for health: A global perspective","volume":"88","author":"Holick","year":"2013","journal-title":"Mayo Clin. Proc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1159\/000486536","article-title":"Vitamin D: Classic and Novel Actions","volume":"72","author":"Gil","year":"2018","journal-title":"Ann. Nutr. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s00198-005-1867-7","article-title":"Estimates of optimal vitamin D status","volume":"16","author":"Heaney","year":"2005","journal-title":"Osteoporos. Int."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kassai, M.S., Cafeo, F.R., Affonso-Kaufman, F.A., Suano-Souza, F.I., and Sarni, R.O.S. (2018). Vitamin D plasma concentrations in pregnant women and their preterm newborns. BMC Pregnancy Childbirth, 18.","DOI":"10.1186\/s12884-018-2045-1"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Qin, L.L., Lu, F.G., Yang, S.H., Xu, H.L., and Luo, B.A. (2016). Does Maternal Vitamin D Deficiency Increase the Risk of Preterm Birth: A Meta-Analysis of Observational Studies. Nutrients, 8.","DOI":"10.3390\/nu8050301"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/jog.13239","article-title":"Vitamin D and risk of preterm birth: Up-to-date meta-analysis of randomized controlled trials and observational studies","volume":"43","author":"Zhou","year":"2017","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1177\/1759720X17706453","article-title":"Vitamin D in pregnancy: Current perspectives and future directions","volume":"9","author":"Kiely","year":"2017","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.gene.2004.05.014","article-title":"Genetics and biology of vitamin D receptor polymorphisms","volume":"338","author":"Uitterlinden","year":"2004","journal-title":"Gene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ejogrb.2014.03.008","article-title":"Vitamin D receptor polymorphism FokI is associated with spontaneous idiopathic preterm birth in an Israeli population","volume":"177","author":"Manzon","year":"2014","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Barchitta, M., Maugeri, A., and La Rosa, M.C. (2018). Single Nucleotide Polymorphisms in Vitamin D Receptor Gene Affect Birth Weight and the Risk of Preterm Birth: Results From the \u201cMamma &Bambino\u201d Cohort and A Meta-Analysis. Nutrients, 10.","DOI":"10.3390\/nu10091172"},{"key":"ref_24","first-page":"1276","article-title":"Relationship between vitamin D receptor gene polymorphism and preterm birth","volume":"36","author":"Cai","year":"2016","journal-title":"Nan Fang. Yi Ke Da XueXueBao"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.gene.2017.10.087","article-title":"Vitamin D receptor (VDR) polymorphisms are associated to spontaneous preterm birth and maternal aspects","volume":"642","author":"Javorski","year":"2018","journal-title":"Gene"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"763","DOI":"10.5603\/GP.2016.0084","article-title":"Influence of Apa1 (rs7975232), Taq1 (rs731236) and Bsm1 (rs154410) polymorphisms of vitamin D receptor on preterm birth risk in the Polish population","volume":"87","author":"Kalinka","year":"2016","journal-title":"Ginekol. Pol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00404-017-4412-y","article-title":"Maternal-fetal vitamin D receptor polymorphisms significantly associated with preterm birth","volume":"296","author":"Rosenfeld","year":"2017","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Dutra, L.V., Affonso-Kaufman, F.A., Cafeo, F.R., Kassai, M.S., Barbosa, C.P., Santos Figueiredo, F.W., Suano-Souza, F.I., and Bianco, B. (2019). Association between vitamin D plasma concentrations and VDR gene variants and the risk of premature birth. BMC Pregnancy Childbirth, 20.","DOI":"10.1186\/s12884-019-2671-2"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1317S","DOI":"10.1093\/ajcn\/71.5.1317s","article-title":"Perinatal metabolism of vitamin D","volume":"71","author":"Salle","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.abb.2011.11.018","article-title":"Vitamin D, the placenta and pregnancy","volume":"523","author":"Liu","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s00198-012-2062-2","article-title":"Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: A controlled cohort study","volume":"24","author":"Streym","year":"2013","journal-title":"Osteoporos. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e26303","DOI":"10.1097\/MD.0000000000026303","article-title":"Systematic review and meta-analysis of vitamin D deficiency in different pregnancy on preterm birth: Deficiency in middle pregnancy might be at risk","volume":"100","author":"Lian","year":"2021","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Murthi, P., Yong, H.E., Ngyuen, T.P., Ellery, S., Singh, H., Rahman, R., Dickinson, H., Walker, D.W., Davies-Tuck, M., and Wallace, E.M. (2016). Role of the Placental Vitamin D Receptor in Modulating Feto-Placental Growth in Fetal Growth Restriction and Preeclampsia-Affected Pregnancies. Front. Physiol., 7.","DOI":"10.3389\/fphys.2016.00043"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00109-015-1267-1","article-title":"Placental vitamin D receptor expression is decreased in human idiopathic fetal growth restriction","volume":"93","author":"Nguyen","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/CEJ.0000000000000132","article-title":"Meta-analysis on vitamin D receptor and cancer risk: Focus on the role of TaqI, ApaI and Cdx2 polymorphisms","volume":"25","author":"Serrano","year":"2016","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_36","first-page":"294","article-title":"The involvement of vdr promoter methylation, cdx-2 vdr polymorphism and vitamin D levels in male infertility","volume":"13","author":"Vladoiu","year":"2017","journal-title":"Acta Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e13530","DOI":"10.1111\/srt.13530","article-title":"The CDX2 G allele and the FoKI F allele of the VDR gene are more prevalent and related to changes in vitamin D levels in patients with psoriasis vulgaris: A pilot study","volume":"29","author":"AbdElneam","year":"2023","journal-title":"Skin Res. Technol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.1158\/1078-0432.CCR-07-4894","article-title":"VDR and SRD5A2 polymorphisms combine to increase risk for prostate cancer in both non-Hispanic White and Hispanic White men","volume":"14","author":"Torkko","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Iqbal, M.U., Khan, T.A., and Maqbool, S.A. (2015). Vitamin D receptor Cdx-2 polymorphism and premenopausal breast cancer risk in southern Pakistani patients. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122657"},{"key":"ref_40","first-page":"9","article-title":"Possible association of Vitamin D receptor, caudal-related homeobox 2 polymorphism with the risk of cancer","volume":"15","author":"Rehman","year":"2021","journal-title":"Int. J. Health Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1359\/jbmr.2001.16.7.1256","article-title":"The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene","volume":"16","author":"Arai","year":"2001","journal-title":"J. Bone Miner. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gwenzi, T., Schrotz-King, P., Sch\u00f6ttker, B., Hoffmeister, M., and Brenner, H. (2023). Vitamin D Status, Cdx2 Genotype, and Colorectal Cancer Survival: Population-Based Patient Cohort. Nutrients, 15.","DOI":"10.3390\/nu15122717"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1080\/07315724.2016.1218803","article-title":"Association between Vitamin D Receptor Polymorphism and Serum Vitamin D Levels in Children with Low-Energy Fractures","volume":"36","author":"Galicka","year":"2017","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1365-2133.2012.11132.x","article-title":"The association of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D levels with generalized vitiligo","volume":"167","author":"Li","year":"2012","journal-title":"Br. J. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7829","DOI":"10.1038\/s41598-019-44373-2","article-title":"Vitamin D Receptor gene polymorphisms and plasma levels are associated with lumbar disc degeneration","volume":"9","author":"Yang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.gene.2016.05.004","article-title":"Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder","volume":"588","author":"Camkurt","year":"2016","journal-title":"Gene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.2217\/pgs-2016-0045","article-title":"Relationship between vitamin D receptor gene polymorphisms, cardiovascular risk factors and adiponectin in a healthy young population","volume":"17","author":"Hajj","year":"2016","journal-title":"Pharmacogenomics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11712\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:25:11Z","timestamp":1760113511000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,31]]},"references-count":47,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111712"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111712","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,31]]}}}