Vitamin D, vitamin D receptor gene polymorphisms, and inflammatory bowel disease outcomes: From molecular mechanisms to clinical application

Table 1 Clinical studies investigating the relationship between single-nucleotide polymorphisms, vitamin D receptor, and vitamin D in inflammatory bowel diseases

Ref.	Aims	Study type	Main findings
Hughes et al[56], 2011	To determine if common VDR polymorphisms affected IBD risk in an Irish population	Cohort - observational, n = 1359 (413 CD, 247 UC, and 699 healthy controls)	No significant correlation was observed between VDR polymorphisms (FokI, BsmI, ApaI, and TaqI) and the risk of IBD
Xia et al[44], 2016	To investigate the association of VDR polymorphisms and 25(OH)D levels in Chinese patients with CD	Case-control - observational, n = 297 patients with CD and 446 controls	The BsmI and TaqI SNPs were less prevalent in CD patients than in controls
			The AAC haplotype, formed by BsmI, ApaI, and TaqI, was less prevalent in patients with CD
			Vitamin D deficiency in patients with CD interacted with the mutant genotypes of FokI (TC + CC), ApaI (CA + AA), and TaqI (TC + CC)
Szymczak-Tomczak et al[50], 2019	To investigate the association of the TaqI polymorphism (rs731236, c.1056T>C) in the VDR gene with serum vitamin D concentration and BMD in patients with IBD	Observational, n = 172 patients with IBD (85 with CD and 87 with UC) and 39 healthy controls	Serum vitamin D levels in patients with IBD were not reduced compared with healthy controls
			Patients with UC carrying the tt TaqI SNP of the VDR gene exhibited higher femoral neck BMD than those with the TT and Tt genotypes (P = 0.02)
			The tt genotype was more frequent in patients with UC than in controls and patients with CD (23% vs 7.7% and 16.5%, respectively)
Gisbert-Ferrándiz et al[49], 2024	To analyze the association of BsmI, ApaI, TaqI, and FokI SNPs in the VDR gene with the clinical characteristics of CD	Observational, n = 115 patients with CD and 20 healthy individuals	The aa genotype of the ApaI SNP in the VDR gene is associated with a lower risk of perianal fistulas in CD
			No significant association was detected between the FokI, BsmI, ApaI, and TaqI VDR gene polymorphisms and the risk of developing CD compared with healthy controls
			Patients with the aa genotype of ApaI had a lower risk of perianal fistulas than the other genotypes (Aa/AA) (P = 0.0360)
			The AA genotype of ApaI was associated with an increased risk of penetrating behavior compared with the combination of the other two genotypes (P = 0.0347)
			The BB genotype of BsmI was significantly associated with an increased risk of penetrating behavior compared with the combination of the other two genotypes (P = 0.0235)
Śledzińska et al[13], 2024	To investigate the correlation between the incidence of VDR gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions)	Observational, n = 109 children (34 with CD and 28 with UC) and 47 healthy controls	Increased likelihood of developing IBD in heterozygotes for the Cdx2 polymorphism (rs11568820) (OR = 2.3, 95%CI: 0.88-6.18, P = 0.04)
			Heterozygotes for the BsmI polymorphism (rs1544410) hada 207-fold higher likelihood of developing IBD (OR = 2.07, 95%CI: 0.89-4.82, P = 0.048)
			GG homozygotes for the ApaI polymorphism (rs7975232) (OR = 0.47, 95%CI: 0.21-1.04, P = 0.05) and TT homozygotes for the TaqI polymorphism (rs731236) (OR = 0.47, 95%CI: 0.21-1.03, P = 0.04) were associated with a reduced likelihood of developing IBD
			Correlation between vitamin D levels and the BsmI polymorphism (rs1544410) was observed in patients with IBD (P = 0.04) and in patients with CD (P = 0.04)
Kafentzi et al[18], 2025	To investigate how ApaI, BsmI, TaqI, and FokI SNPs affect IBD phenotype and progression	Observational, n = 144 patients (76 with CD and 68 with UC)	The aa genotype of ApaI was independently associated with a reduced risk of IBD-related hospitalization (OR = 0.17; P = 0.013) and a decreased risk of IBD-related surgery (OR = 0.055; P = 0.014)
			The AA genotype of ApaI was associated with higher rates of penetrating CD (B3) (36.7% vs 8.7%; P = 0.012)
			The ff genotype of FokI was associated with disease location, predisposing to upper gastrointestinal tract involvement (36.4% vs 7.7%; P = 0.044) or colonic participation (90.9% vs 50.8%; P = 0.038)
			All patients carrying the aa genotype were less likely to experience steroid-refractory or steroid-dependent disease (11.1% vs 37.6%; P = 0.022)
			The TT genotype of TaqI was independently associated with increased risk of hospitalization (OR = 4.79; P = 0.044)

VDR: Vitamin D receptor; IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; BMD: Bone mineral density; SNP: Single-nucleotide polymorphism; OR: Odds ratio; CI: Confidence interval.

Table 2 Thresholds for classifying vitamin D insufficiency and deficiency according to major guidelines and vitamin D supplementation protocols

Organization	Reference range (ng/mL)	Toxicity (ng/mL)	Supplementation
World Health Organization[74]	< 10 - deficiency. < 20 - insufficiency	-	-
Endocrine Society[75]	> 20 - sufficient	> 60	-
Institute of Medicine[76]	< 12 - deficiency. < 20 - insufficiency	> 50
European Society for Clinical Nutrition and Metabolism[71]	No defined cutoff	-	-
Brazilian Society of Endocrinology and Metabolism[77]	30-60 ng/mL - sufficient	> 100	-
Position Statement of the Brazilian Association of Nutrology (Abran)[78]	> 40 - sufficient	> 100	6000 IU/day or 50000 IU/week in case of deficiency
British Society of Gastroenterology[69]	< 20 - deficiency	-	800-1000 mg/day of calcium and 800 IU/day of vitamin D for patients with active disease and receiving corticosteroids
Central and Eastern European Expert Consensus[79]	< 20 - deficiency. < 30 - insufficiency	> 100	6000-10000 IU/day in case of deficiency
Second Brazilian Consensus on Managing Crohn's Disease in Adults[70]	No defined cutoff	-	800-1000 mg/day of calcium and 800 IU/day of vitamin D in case of deficiency
Endocrine Society - Update[80]	No defined cutoff	-	-
European Crohn’s and Colitis Organization[67]	< 30 - deficiency	-	-
European Crohn’s and Colitis Organization in collaboration with: European Society of Gastrointestinal and Abdominal Radiology; European Society of Pathology and International Bowel Ultrasonography Group[68]	< 20 - insufficiency	-	-