Association of Vitamin D and Genetic Variation in IBD

Abstract

Purpose: Both environmental and genetic factors increase susceptibility to CD. Advances in an understanding of the genes associated with CD susceptibility have emphasized the role of autophagy and Paneth cell function in CD pathogenesis but not in the development of UC. More recently an association between vitamin D (VitD) deficiency and the development of CD has been identified. Methods: We identified 377 IBD (256 CD and 106 UC) patients genotyped with the immunochip with serum VitD (25-OH vitamin D) measurements collated by chart review. Linear regression was used to evaluate the relationship between VitD and genotype. Top 3 principle components in the population stratification analysis were included as covariates and permutation test was performed in the worth-noting variants to retain the type I error rate. SNPs with minor allele frequencies > 0.025 were included for analyses. Results: We report associations with a p value > 10-4. In the analyses with all the IBD patients genetic variations at RBM5 (involved in apoptotic pathways) (p=5.04E-05), MYOZ3/IRGM (calcineurin signaling/autophagy) (p=1.32E-05), LYN (regulator of adaptive/innate immune responses) (p=4.98E-05), and DLG2 (scaffolding protein) (p=7.77E-05) were observed to be associated with VitD. In total, 9 regions met our criteria for reporting in the CD analyses including MYOZ3/IRGM and LYN from the IBD analyses. In addition the CD-VitD genetic associations included: TLR4 (innate immunity) (p=1.40E-7); MAFB (macrophage development) (p=4.64E-05); PTPRC (T cell activation); and SIGLEC12 (cell adhesion) (p=6.83E-05). These were no associations of P > 1.0E-04 with VitD and UC. Conclusion: We have identified significant associations in IBD and CD between vitamin D and genetic variations in genes of potential significant relevance to IBD pathogenesis. Most notable are the associations with TLR4 (known to act with vitamin D in the development of animal models of chronic colitis) and IRGM (substantiating the potential role of vitamin D in the autophagy pathways).