P1308 The ApaI polymorphism in the vitamin D receptor (VDR) gene affects the phenotype and complications of Crohn’s disease
Authors: Tsounis E , Kafentzi T , Tourkochristou E , Avramopoulou E , Aggeletopoulou I , Geramoutsos G , Sotiropoulos C , Thomopoulos K , Theocharis G , Triantos C 
Published: January 2025

Background

Vitamin D, through its receptor (VDR), exerts pleiotropic effects that support gut barrier homeostasis. Dysregulation of the vitamin D/VDR signaling is implicated in the pathogenesis of inflammatory bowel disease (IBD).1,2 Our study aims to elucidate how the ApaI, BsmI, TaqI, and FokI single-nucleotide polymorphisms (SNPs) influence disease phenotype and the development of related outcomes.

Methods

In this observational study, 76 patients with Crohn’s disease (CD) and 68 with ulcerative colitis (UC) were consecutively enrolled. Blood samples were collected, and genomic DNA was extracted. VDR SNPs were genotyped via predesigned TaqMan SNP assays on a Step One Plus PCR system. Fisher’s exact test was used for contingency table analysis. A multivariate logistic regression with backward selection evaluated adverse outcome risk, including variables with p&lt;0.05 from univariate analysis.

Results

Genotype frequencies for all SNPs were in Hardy-Weinberg equilibrium, with no differences observed in distribution between CD and UC groups. The AA genotype of ApaI was accompanied by higher rates of penetrating (B3) disease in CD (36.7% vs. 8.7%; p=0.006) compared to the Aa/aa genotypes. Conversely, Aa/aa genotype carriers were more likely to develop stenotic (B2) CD (67.4% vs. 40%; p=0.032). The FokI SNP was associated with disease location, with the ff genotype being more common among patients with upper GI involvement (L4) (44.4% vs. 10.4%; p=0.022) and colonic disease (23.8% vs. 2.9%; p=0.018) compared to the FF/Ff genotypes. Additionally, patients harboring the f allele (Ff/ff) experienced higher rates of steroid-refractory or steroid-dependent CD (35.5% vs. 12.9%; p=0.035). In the overall cohort, the AA/Aa genotypes were also linked to failure to respond to steroids (37.6% vs. 11.1%; p=0.011). In CD, the risk of IBD-related hospitalization and surgery was significantly higher in patients homozygous for the dominant ApaI and TaqI SNPs than in those carrying the corresponding recessive alleles. Patients with the AA genotype demonstrated the highest surgery rates, followed by those with the Aa/aa genotype (56.7% vs. 23.9%; p=0.007) and then the aa genotype (56.7% vs. 7.1%; p=0.003), suggesting a possible additive effect of the ApaI SNP. In multivariate analysis, the aa genotype showed a protective effect against hospitalization (aOR=0.17; p=0.013), whereas the TT genotype was identified as an independent risk factor for hospitalization (aOR=4.79; p=0.044). Moreover, the aa genotype was independently associated with a decreased risk of IBD-related surgery (aOR=0.055; p= 0.014).

Conclusion

VDR SNPs, particularly ApaI, influence disease phenotype, progression, and treatment response in CD.

References

1.Aggeletopoulou I, Marangos M, Assimakopoulos SF, Mouzaki A, Thomopoulos K, Triantos C. Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis. Am J Pathol. 2023;193(6):656-668. doi:10.1016/j.ajpath.2023.02.004

2.Triantos C, Aggeletopoulou I, Mantzaris GJ, Mouzaki A. Molecular basis of vitamin D action in inflammatory bowel disease. Autoimmun Rev. 2022;21(8):103136. doi:10.1016/j.autrev.2022.103136