P1143 Impact of vitamin D metabolism gene polymorphisms on therapeutic efficacy of vedolizumab and ustekinumab in Inflammatory Bowel Disease
Authors: De Vita F , Ribaldone G R , D'Avolio A , Infusino V , Antonucci M , Caviglia G P , Armandi A , Ceccarelli L , Costa F , Bottari A , Fe P , Bertani L , Cusato J 
Published: January 2025

Abstract

Background
Vitamin D (VD) is a crucial biological agent with immunoregulatory and anti-inflammatory properties. There is growing interest in identifying genes regulated by VD to explore its therapeutic potential in various diseases, including Inflammatory Bowel Disease (IBD). Understanding single nucleotide polymorphisms (SNPs) and genotypes of VD-associated genes is essential for predicting therapeutic outcomes of biologic treatments and personalizing IBD management. This study aimed to evaluate the role of VD-related genetics in predicting the clinical response of patients with Crohn's disease (CD) and ulcerative colitis (UC) to biologics vedolizumab (VDZ) and ustekinumab (UST) after 12 months of therapy (T12), and to assess the achievement of fecal calprotectin (FC) levels &lt;250 mg/kg, a surrogate marker for mucosal healing.

Methods
A prospective study was conducted including 103 patients (67 with CD, 36 with UC) treated with VDZ (40/103) and UST (63/103). SNPs of the genes CYP24A1, GC, CYP27B1, VDR ApaI, VDR Cdx2, VDR BsmI and VDR TaqI were analyzed using polymerase chain reaction (PCR) and correlated with clinical and laboratory outcomes through contingency tables and univariate logistic regression analysis for each SNP.

Results
UST therapy showed a higher clinical response rate at T12 than VDZ (85.7% vs. 67.5%, OR 2.89, 95% CI 1.10-7.60, p=0.03). A significant association was observed between response at T3 and T12 (p=0.0002, OR 6.91, 95% CI: 2.48-19.30). The GC 1296 AC polymorphism was a negative predictor of response at T12, with 63.6% of non-responders carrying this genotype. Treatment stratification confirmed that in VDZ-treated patients, AC heterozygotes were less likely to achieve the primary outcome (46.7%), with an OR of 4.57 (95% CI: 1.12-18.73, p=0.04). CYP24A1 8620 AG was a statistically significant negative predictor for achieving FC levels &lt; 250 mg/kg (p=0.045). Moreover, CYP24A1 22776 CT and VDR Cdx2 GG were associated with a higher likelihood of presenting with CD rather than UC (OR = 3.40, 95% CI: 1.35 - 8.52, p-value = 0.009 and OR = 3.74, 95% CI = 1.02-13.77, p-value = 0.047, respectively). In addition, SNPs in the CYP27B1 gene, -1260 GT and +2838 CT, were significantly associated with non-ileal CD (non-L1 CD), increasing the probability of non-L1 presentation by 3-fold (OR = 3.13, 95% CI: 0.98-10.01, p-value = 0.054) and 7-fold (OR = 7.02, 95% CI: 1.44-34.25, p-value = 0.01), respectively.

Conclusion
In conclusion, this study identifies associations between polymorphisms in the vitamin D pathway and clinical and laboratory responses to VDZ or UST after 12 months of therapy, IBD phenotype, and CD localization. Further research is needed to validate these findings and to develop personalized IBD treatment strategies.

References
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