Polymorphism in the Vitamin D Receptor Gene Decreases the Risk of Perianal Fistulas in Crohn's Disease

Overview

Journal Nutrients

Date 2024 Oct 26

PMID 39458479

Authors

Laura Gisbert-Ferrandiz

Jorge Llau

Dolores Ortiz-Masia

Jesus Cosin-Roger

Dulce Carolina Macias-Ceja

Joaquin Hinojosa

Sara Calatayud

Maria Dolores Barrachina

Affiliations

Soon will be listed here.

Abstract

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's disease (CD) risk, and patients carrying the polymorphism in this gene run a higher risk of developing a penetrating behavior.

Aims: We analyzed the association of , , , and SNPs in the gene with the clinical characteristics of CD.

Methods: Four polymorphisms identified in the gene (, , , and ) were genotyped in blood samples from CD patients (n = 115) by using PCR-RFLP. The disease's 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 and both and , which in turn were strongly associated. Homozygosis or heterozygosis for the a allele of the SNP or b allele of the 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 SNP in the gene is associated with a lower risk of perianal fistulas in CD and a reduced expression of fibrotic and inflammatory markers in intestinal fibroblasts.

Citing Articles

Genetic Polymorphisms (ApaI, FokI, BsmI, and TaqI) of the Vitamin D Receptor (VDR) Influence the Natural History and Phenotype of Crohn's Disease.

Kafentzi T, Tsounis E, Tourkochristou E, Avramopoulou E, Aggeletopoulou I, Geramoutsos G Int J Mol Sci. 2025; 26(5).

PMID: 40076474 PMC: 11899612. DOI: 10.3390/ijms26051848.

References

Macias-Ceja D, Ortiz-Masia D, Salvador P, Gisbert-Ferrandiz L, Hernandez C, Hausmann M . Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol. 2018; 12(1):178-187. DOI: 10.1038/s41385-018-0087-3. View

Naderi N, Farnood A, Habibi M, Derakhshan F, Balaii H, Motahari Z . Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2008; 23(12):1816-22. DOI: 10.1111/j.1440-1746.2008.05525.x. View

Annese V . Genetics and epigenetics of IBD. Pharmacol Res. 2020; 159:104892. DOI: 10.1016/j.phrs.2020.104892. View

Gisbert-Ferrandiz L, Cosin-Roger J, Hernandez C, Macias-Ceja D, Ortiz-Masia D, Salvador P . 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. 2020; 202:105720. DOI: 10.1016/j.jsbmb.2020.105720. View

Xia S, Lin X, Guo M, Zhang D, Zheng S, Jiang L . Association of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D levels with Crohn's disease in Chinese patients. J Gastroenterol Hepatol. 2015; 31(4):795-801. DOI: 10.1111/jgh.13221. View

Simmons J, Mullighan C, Welsh K, Jewell D . Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut. 2000; 47(2):211-4. PMC: 1728007. DOI: 10.1136/gut.47.2.211. View

Martin K, Radlmayr M, Borchers R, Heinzlmann M, Folwaczny C . Candidate genes colocalized to linkage regions in inflammatory bowel disease. Digestion. 2002; 66(2):121-6. DOI: 10.1159/000065592. View

Geldof J, Iqbal N, LeBlanc J, Anandabaskaran S, Sawyer R, Buskens C . Classifying perianal fistulising Crohn's disease: an expert consensus to guide decision-making in daily practice and clinical trials. Lancet Gastroenterol Hepatol. 2022; 7(6):576-584. DOI: 10.1016/S2468-1253(22)00007-3. View

Lye M, Tor Y, Tey Y, Shahabudin A, Loh S, Ibrahim N . BsmI-ApaI-TaqI TAC (BAt) Haplotype of Vitamin D Receptor Gene Is Associated with Increased Risk of Major Depressive Disorder. J Mol Neurosci. 2020; 71(5):981-990. DOI: 10.1007/s12031-020-01719-0. View

10.

Cao S, Colonna M, Deepak P . Pathogenesis of Perianal Fistulising Crohn's Disease: Current Knowledge, Gaps in Understanding, and Future Research Directions. J Crohns Colitis. 2023; 17(6):1010-1022. DOI: 10.1093/ecco-jcc/jjad008. View

11.

Xue L, Xu K, Zhang W, Wang Q, Wu J, Wang X . Associations between vitamin D receptor polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. Inflamm Bowel Dis. 2012; 19(1):54-60. DOI: 10.1002/ibd.22966. View

12.

Householder S, Picoraro J . Diagnosis and Classification of Fistula from Inflammatory Bowel Disease and Inflammatory Bowel Disease-Related Surgery. Gastrointest Endosc Clin N Am. 2022; 32(4):631-650. DOI: 10.1016/j.giec.2022.04.003. View

13.

Bakke D, Sun J . Ancient Nuclear Receptor VDR With New Functions: Microbiome and Inflammation. Inflamm Bowel Dis. 2018; 24(6):1149-1154. PMC: 6148749. DOI: 10.1093/ibd/izy092. View

14.

Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg M . Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management?. Gastroenterology. 2022; 162(5):1370-1382. DOI: 10.1053/j.gastro.2021.12.246. View

15.

Ferrer-Suay S, Alonso-Iglesias E, Tortajada-Girbes M, Carrasco-Luna J, Codoner-Franch P . Vitamin D receptor gene and polymorphisms and its association with inflammation and oxidative stress in vitamin D sufficient Caucasian Spanish children. Transl Pediatr. 2021; 10(1):103-111. PMC: 7882298. DOI: 10.21037/tp-20-198. View

16.

Seco-Cervera M, Ortiz-Masia D, Macias-Ceja D, Coll S, Gisbert-Ferrandiz L, Cosin-Roger J . Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis. Biochim Biophys Acta Mol Basis Dis. 2023; 1870(2):166966. DOI: 10.1016/j.bbadis.2023.166966. View

17.

Yang W, Yu T, Cong Y . Stromal Cell Regulation of Intestinal Inflammatory Fibrosis. Cell Mol Gastroenterol Hepatol. 2024; 17(5):703-711. PMC: 10958116. DOI: 10.1016/j.jcmgh.2024.01.007. View

18.

Luo Y, Shu X, Zhao H, Yu J, Ma M, Chen J . [Association between vitamin D receptor gene polymorphisms and pediatric Crohn's disease in China: a study based on gene sequencing]. Zhongguo Dang Dai Er Ke Za Zhi. 2013; 15(11):1006-8. View

19.

Gisbert-Ferrandiz L, Cosin-Roger J, Hernandez C, Macias-Ceja D, Ortiz-Masia D, Salvador P . Diminished Vitamin D Receptor Protein Levels in Crohn's Disease Fibroblasts: Effects of Vitamin D. Nutrients. 2020; 12(4). PMC: 7230839. DOI: 10.3390/nu12040973. View

20.

Limketkai B, Singla M, Rodriguez B, Veerappan G, Betteridge J, Ramos M . Levels of Vitamin D Are Low After Crohn's Disease Is Established But Not Before. Clin Gastroenterol Hepatol. 2019; 18(8):1769-1776.e1. PMC: 7163919. DOI: 10.1016/j.cgh.2019.09.034. View