{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:25:13Z","timestamp":1788431113898,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T00:00:00Z","timestamp":1728864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"European Regional Development Fund of the European Union [ERDF]","doi-asserted-by":"publisher","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"European Regional Development Fund of the European Union [ERDF]","doi-asserted-by":"publisher","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"European Regional Development Fund of the European Union [ERDF]","doi-asserted-by":"publisher","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"European Regional Development Fund of the European Union [ERDF]","doi-asserted-by":"publisher","award":["EHD19PI05"],"award-info":[{"award-number":["EHD19PI05"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"European Regional Development Fund of the European Union [ERDF]","doi-asserted-by":"publisher","award":["CIPROM2021\/044"],"award-info":[{"award-number":["CIPROM2021\/044"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"ERDF A way of making Europe","doi-asserted-by":"publisher","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"ERDF A way of making Europe","doi-asserted-by":"publisher","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"ERDF A way of making Europe","doi-asserted-by":"publisher","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"ERDF A way of making Europe","doi-asserted-by":"publisher","award":["EHD19PI05"],"award-info":[{"award-number":["EHD19PI05"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"ERDF A way of making Europe","doi-asserted-by":"publisher","award":["CIPROM2021\/044"],"award-info":[{"award-number":["CIPROM2021\/044"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CIBERehd","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}]},{"name":"CIBERehd","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}]},{"name":"CIBERehd","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}]},{"name":"CIBERehd","award":["EHD19PI05"],"award-info":[{"award-number":["EHD19PI05"]}]},{"name":"CIBERehd","award":["CIPROM2021\/044"],"award-info":[{"award-number":["CIPROM2021\/044"]}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PID2022-141011OB-I00"],"award-info":[{"award-number":["PID2022-141011OB-I00"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["EHD19PI05"],"award-info":[{"award-number":["EHD19PI05"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["CIPROM2021\/044"],"award-info":[{"award-number":["CIPROM2021\/044"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Vitamin D, through the activation of its receptor (VDR), plays an immunomodulatory role in the gastrointestinal tract. Single-nucleotide polymorphisms (SNPs) in the VDR gene have been associated with Crohn\u2019s disease (CD) risk, and patients carrying the TaqI polymorphism in this gene run a higher risk of developing a penetrating behavior. Aims: We analyzed the association of BsmI, ApaI, TaqI, and FokI SNPs in the VDR gene with the clinical characteristics of CD. Methods: Four polymorphisms identified in the VDR gene (BsmI, FokI, ApaI, and TaqI) were genotyped in blood samples from CD patients (n = 115) by using PCR-RFLP. The disease\u2019s location and behavior and the presence of perianal fistulas were collected from each patient. Intestinal fibroblasts from ileal resections of CD patients (n = 10) were genotyped, and the expression of fibrotic and inflammatory markers was analyzed by RT-PCR. Results: The data reveal no association between any of the polymorphisms and CD risk. A strong linkage disequilibrium was detected between TaqI and both ApaI and BsmI, which in turn were strongly associated. Homozygosis or heterozygosis for the a allele of the ApaI SNP or b allele of the BsmI SNP was significantly associated with a lower risk of a penetrating behavior, while the aa genotype was associated with a lower risk of perianal fistulas. Fibroblasts carrying the aa genotype expressed lower levels of fibrotic and inflammatory markers. Conclusion: The aa genotype of the ApaI SNP in the VDR gene is associated with a lower risk of perianal fistulas in CD and a reduced expression of fibrotic and inflammatory markers in intestinal fibroblasts.<\/jats:p>","DOI":"10.3390\/nu16203485","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T12:44:31Z","timestamp":1728909871000},"page":"3485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ApaI Polymorphism in the Vitamin D Receptor Gene Decreases the Risk of Perianal Fistulas in Crohn\u2019s Disease"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2007-8716","authenticated-orcid":false,"given":"Laura","family":"Gisbert-Ferr\u00e1ndiz","sequence":"first","affiliation":[{"name":"Departamento de Farmacolog\u00eda and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Llau","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7924-9962","authenticated-orcid":false,"given":"Dolores","family":"Ortiz-Masia","sequence":"additional","affiliation":[{"name":"Departamento de Medicina and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Cos\u00edn-Roger","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dulce Carolina","family":"Macias-Ceja","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Hinojosa","sequence":"additional","affiliation":[{"name":"Servicio de Gastroenterolog\u00eda, Hospital de Manises, 46940 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9675-2423","authenticated-orcid":false,"given":"Sara","family":"Calatayud","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Dolores","family":"Barrachina","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda and CIBERehd, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1053\/j.gastro.2021.12.246","article-title":"Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management?","volume":"162","author":"Verstockt","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.giec.2022.04.003","article-title":"Diagnosis and Classification of Fistula from Inflammatory Bowel Disease and Inflammatory Bowel Disease-Related Surgery","volume":"32","author":"Householder","year":"2022","journal-title":"Gastrointest. Endosc. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/S2468-1253(22)00007-3","article-title":"Classifying perianal fistulising Crohn\u2019s disease: An expert consensus to guide decision-making in daily practice and clinical trials","volume":"7","author":"Geldof","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bernstein, C.N., Panaccione, R., Nugent, Z., Marshall, D.A., Kaplan, G.G., Vanner, S., Dieleman, L.A., Graff, L.A., Otley, A., and Jones, J. (2024). Crohn\u2019s Disease Phenotypes and Associations with Comorbidities, Surgery Risk, Medications and Nonmedication Approaches: The MAGIC in IMAGINE Study. Inflamm. Bowel Dis., izae055.","DOI":"10.1093\/ibd\/izae055"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104892","DOI":"10.1016\/j.phrs.2020.104892","article-title":"Genetics and epigenetics of IBD","volume":"159","author":"Annese","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1093\/ibd\/izy092","article-title":"Ancient Nuclear Receptor VDR with New Functions: Microbiome and Inflammation","volume":"24","author":"Bakke","year":"2018","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1159\/000065592","article-title":"Candidate genes colocalized to linkage regions in inflammatory bowel disease","volume":"66","author":"Martin","year":"2002","journal-title":"Digestion"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1136\/gut.47.2.211","article-title":"Vitamin D receptor gene polymorphism: Association with Crohn\u2019s disease susceptibility","volume":"47","author":"Simmons","year":"2000","journal-title":"Gut"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/ibd.22966","article-title":"Associations between vitamin D receptor polymorphisms and susceptibility to ulcerative colitis and Crohn\u2019s disease: A meta-analysis","volume":"19","author":"Xue","year":"2013","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.4238\/2014.April.8.2","article-title":"Polymorphisms of the vitamin D receptor gene and the risk of inflammatory bowel disease: A meta-analysis","volume":"13","author":"Wang","year":"2014","journal-title":"Genet. Mol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1111\/jgh.13221","article-title":"Association of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D levels with Crohn\u2019s disease in Chinese patients","volume":"31","author":"Xia","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1111\/j.1440-1746.2008.05525.x","article-title":"Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease","volume":"23","author":"Naderi","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_13","first-page":"1006","article-title":"Association between vitamin D receptor gene polymorphisms and pediatric Crohn\u2019s disease in China: A study based on gene sequencing","volume":"15","author":"Luo","year":"2013","journal-title":"Zhongguo Dang Dai Er Ke Za Zhi"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1016\/j.cgh.2019.09.034","article-title":"Levels of Vitamin D Are Low After Crohn\u2019s Disease Is Established but Not Before","volume":"18","author":"Limketkai","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1093\/ibd\/izy094","article-title":"A Single Nucleotide Polymorphism in the Vitamin D Receptor Gene Is Associated with Decreased Levels of the Protein and a Penetrating Pattern in Crohn\u2019s Disease","volume":"24","author":"Salvador","year":"2018","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cusato, J., Cafasso, C., Antonucci, M., Palermiti, A., Manca, A., Caviglia, G.P., Vernero, M., Armandi, A., Saracco, G.M., and D\u2019Avolio, A. (2024). Correlation between Polymorphisms of Vitamin D Metabolism Genes and Perianal Disease in Crohn\u2019s Disease. Biomedicines, 12.","DOI":"10.3390\/biomedicines12020320"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gisbert-Ferrandiz, L., Cosin-Roger, J., Hernandez, C., Macias-Ceja, D.C., Ortiz-Masia, D., Salvador, P., Wildenberg, M.E., Esplugues, J.V., Alos, R., and Navarro, F. (2020). The vitamin D receptor Taq I polymorphism is associated with reduced VDR and increased PDIA3 protein levels in human intestinal fibroblasts. J. Steroid Biochem. Mol. Biol., 202.","DOI":"10.1016\/j.jsbmb.2020.105720"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/s41385-018-0087-3","article-title":"Succinate receptor mediates intestinal inflammation and fibrosis","volume":"12","author":"Salvador","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1097\/MEG.0b013e328349283e","article-title":"Common variation in the vitamin D receptor gene and risk of inflammatory bowel disease in an Irish case-control study","volume":"23","author":"Hughes","year":"2011","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s12031-020-01719-0","article-title":"BsmI-ApaI-TaqI TAC (BAt) Haplotype of Vitamin D Receptor Gene Is Associated with Increased Risk of Major Depressive Disorder","volume":"71","author":"Lye","year":"2021","journal-title":"J. Mol. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1093\/ecco-jcc\/jjad008","article-title":"Pathogenesis of Perianal Fistulising Crohn\u2019s Disease: Current Knowledge, Gaps in Understanding, and Future Research Directions","volume":"17","author":"Cao","year":"2023","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101251","DOI":"10.1016\/j.mam.2024.101251","article-title":"Recent advances in intestinal fibrosis","volume":"96","author":"Lenti","year":"2024","journal-title":"Mol. Asp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.jcmgh.2024.01.007","article-title":"Stromal Cell Regulation of Intestinal Inflammatory Fibrosis","volume":"17","author":"Yang","year":"2024","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, H., Zhou, Y., Wen, D., and Wang, J. (2023). Noncoding RNAs: Master Regulator of Fibroblast to Myofibroblast Transition in Fibrosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021801"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.21037\/tp-20-198","article-title":"Vitamin D receptor gene ApaI and FokI polymorphisms and its association with inflammation and oxidative stress in vitamin D sufficient Caucasian Spanish children","volume":"10","year":"2021","journal-title":"Transl. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Seco-Cervera, M., Ortiz-Masia, D., Macias-Ceja, D.C., Coll, S., Gisbert-Ferrandiz, L., Cosin-Roger, J., Bauset, C., Ortega, M., Heras-Moran, B., and Navarro-Vicente, F. (2024). Resistance to apoptosis in complicated Crohn\u2019s disease: Relevance in ileal fibrosis. Biochim. Biophys. Acta Mol. Basis Dis., 1870.","DOI":"10.1016\/j.bbadis.2023.166966"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gisbert-Ferr\u00e1ndiz, L., Cos\u00edn-Roger, J., Hern\u00e1ndez, C., Macias-Ceja, D.C., Ortiz-Masi\u00e1, D., Salvador, P., Esplugues, J.V., Hinojosa, J., Navarro, F., and Calatayud, S. (2020). Diminished Vitamin D Receptor Protein Levels in Crohn\u2019s Disease Fibroblasts: Effects of Vitamin D. Nutrients, 12.","DOI":"10.3390\/nu12040973"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/20\/3485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:13:20Z","timestamp":1760112800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/20\/3485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,14]]},"references-count":27,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["nu16203485"],"URL":"https:\/\/doi.org\/10.3390\/nu16203485","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,14]]}}}