Genetic Variations in Vitamin D Metabolism Genes and the Microbiome, in the Presence of Adverse Environmental Changes, Increase Immune Dysregulation

Review Article

Austin J Nutr Metab. 2015; 2(4): 1026.

Genetic Variations in Vitamin D Metabolism Genes and the Microbiome, in the Presence of Adverse Environmental Changes, Increase Immune Dysregulation

Laing BB¹ and Ferguson LR1,2*

¹Discipline of Nutrition and Dietetics, FMHS, University of Auckland, New Zealand

²Auckland Cancer Society Research Centre, FMHS, University of Auckland, New Zealand

*Corresponding author: Lynnette R Ferguson, Auckland Cancer Society Research Centre, FMHS, University of Auckland, Auckland, New Zealand

Received: July 03, 2015; Accepted: August 06, 2015; Published: August 08, 2015

Abstract

Vitamin D metabolism in individuals is affected not only by their exposure to the sun or dietary intake of vitamin D, their liver and kidney function and other tissue production, but also by genetic variations in genes associated with vitamin D metabolism. These genes include not only the vitamin D receptor (VDR) genes, but also Group–Specific Component (GC), 7-dehydrocholesterol reductase (DHCR7), cytochrome P450 2R1(CYP2R1), cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), and cytochrome p450 27B1 (CYP27B1). Particular single nucleotide polymorphisms (SNPs) from a number of these genes are being associated with lower or higher circulating vitamin D concentrations. Vitamin D metabolism is also affected by interactions with the individual’s microbiome. Other environmental changes in addition to vitamin D intake, particularly those associated with variations in nutrient intake and exposure to pathogens, can impact on these gene variations associated with vitamin D metabolism. Certain combinations of these, in addition to a lowering of circulating vitamin D, influence immune and metabolic pathways and contribute to immune dysregulation. The current enhancement and interplay of these permutations augurs the rise of chronic conditions in the Western world. To ameliorate this, vitamin D supplementation needs to be tailored to an individual’s genotype in the context of their environment.

Keywords: Genetic Variations; Vitamin D; Immune Dysregulation

Introduction

Vitamin D is a major regulator of gene expression and signaling in most tissues, and insufficiency affects many adults [1,2]. Genetic factors are thought to play a large part in this. Indeed, the genetic contribution to vitamin D status has been estimated to be from 28- 80% [3-5]. A number of particular single nucleotide polymorphisms (SNPs) for vitamin D associated genes or particular combinations of SNPs from genes relating to vitamin D metabolism can be involved in multiple signaling pathways. These pathways can be associated with lower or higher concentrations of circulating vitamin D. These particular SNPs from genes associated with vitamin D are also becoming increasingly relevant in their association with immune disorders.

Vitamin D deficiency is becoming well recognised as having a role in cell proliferation, differentiation, apoptosis and the immune response [6-13]. Vitamin D has been reported to be a significant factor in seventeen varieties of cancer [14-24], through its interactions with signaling pathways [8,21,25-31]. Vitamin D concentrations are also becoming particularly relevant in inflammatory disorders such as Crohn’s disease (CD), one of the common Inflammatory Bowel Diseases (IBD). Vitamin D plays a significant role in anomalous gene interactions, a critical factor in IBD [32-35]. Wang et al. showed that the active form, 1, 25 (OH) 2D3 affects the nucleotide-binding oligomerization domain containing 2 (NOD2) defense beta2 innate immune pathway, often found to be defective in people with CD [36]. Other immune disorders that have been associated with vitamin D are diabetes, coronary heart disease, blood pressure and outcomes of chronic kidney disease [37-49]. Particular variants of genes, the influence of microbiome, vitamin D metabolic pathways associated with them, and how our changing environment impinges on these and exacerbates immune dysfunction are the basis of the following discussion.

The Vitamin D Receptor Gene (VDR)

Most of the roles of the active form of vitamin D (1,25(OH)2D3) are facilitated by the gene VDR. VDR has a number of functions which include the following: it encodes the nuclear hormone receptor for vitamin D; it is a secondary bile acid lithocholic acid receptor which may act to protect the gut against lethal and carcinogenic endobiotics effects; it has a major role in calcium homeostasis; it affects the expression of 1a-hydroxylase (also known as cytochrome p450 27B1 (CYP27B1) which is associated with the conversion of the inactive form of vitamin D, 25(OH)D to the active form 1,25(OH)2D3; it increases the expression of 1,25(OH)2D3 which modulates cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), a protein associated with the degradation of 1,25-dihydroxyvitamin. Mutations in this receptor can also lead to inherited rickets [50-55].

VDR is a major player among the genes involved with vitamin D metabolism because it influences so many other genes. As a member of the nuclear receptor family it directly modulates gene transcription, and is reported to influence the transcription of more than 913 genes [56]. Ramagopalan et al. found 2776 binding sites for VDR in their ChiP-seq defined genome wide map [57].

This influence of VDR on vitamin D concentrations in particular, is far reaching especially as it relates to immune regulation (Figure 1).

Citation: Laing BB and Ferguson LR. Genetic Variations in Vitamin D Metabolism Genes and the Microbiome, in the Presence of Adverse Environmental Changes, Increase Immune Dysregulation. Austin J Nutr Metab. 2015; 2(4): 1026.