Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease

ArticleinPharmacogenetics and Genomics 21(9):559-64 · September 2011with22 Reads
DOI: 10.1097/FPC.0b013e328348f70c · Source: PubMed
Abstract
Inflammatory bowel diseases (IBDs), Crohn's disease, and ulcerative colitis (UC), are multifactorial disorders, characterized by chronic inflammation of the intestine. A number of genetic components have been proposed to contribute to IBD pathogenesis. In this case-control study, we investigated the association between two common vitamin D-binding protein (DBP) genetic variants and IBD susceptibility. These two single nucleotide polymorphisms (SNPs) in exon 11 of the DBP gene, at codons 416 (GAT>GAG; Asp>Glu) and 420 (ACG>AAG; Thr>Lys), have been previously suggested to play roles in the etiology of other autoimmune diseases. Using TaqMan SNP technology, we have genotyped 884 individuals (636 IBD cases and 248 non-IBD controls) for the two DBP variants. On statistical analysis, we observed that the DBP 420 variant Lys is less frequent in IBD cases than in non-IBD controls (allele frequencies, P=0.034; homozygous carrier genotype frequencies, P=0.006). This inverse association between the DBP 420 Lys and the disease remained significant, when non-IBD participants were compared with UC (homozygous carrier genotype frequencies, P=0.022) or Crohn's disease (homozygous carrier genotype frequencies, P=0.016) patients separately. Although the DBP position 416 alone was not found to be significantly associated with IBD, the haplotype DBP_2, consisting of 416 Asp and 420 Lys, was more frequent in the non-IBD population, particularly notably when compared with the UC group (Odds ratio, 4.390). Our study adds DBP to the list of potential genes that contribute to the complex genetic etiology of IBD, and further emphasizes the association between vitamin D homeostasis and intestinal inflammation.
    • "VDBP has other significant functions such as fatty acid transport, the activation of macrophages and the actin scavenging system. Malnutrition may also lower its concentration [61,115116117. Actin is released from cells upon injury, and GC binds actin to clear it from the circulation, thus preventing actin's harmful effects on blood vessels [117]. "
    [Show abstract] [Hide abstract] ABSTRACT: With the endogenous formation of vitamin D being significantly curtailed because of public awareness of skin cancer dangers, attention is turning to dietary sources. Cumulative evidence has implicated vitamin D deficiency in increasing susceptibility to various gastrointestinal disorders, including colorectal cancer, inflammatory bowel diseases, diverticulitis and irritable bowel syndrome. There is also reason to suggest adjunct vitamin D therapy for such diseases. Although there is justification for increasing vitamin D intake overall, optimal intakes will vary among individuals. Genomic technologies have revealed several hundreds of genes associated with vitamin D actions. The nature of these genes emphasizes the potentially negative implications of modulating vitamin D intakes in the absence of complementary human genetic and genomic data, including information on the gut microbiome. However, we are not yet in a position to apply this information. Genomic data (transcriptomics, metabolomics, proteomics and metagenomics) could provide evidence that vitamin D sufficiency has been achieved. We suggest that there is an increasingly strong case for considering the more widespread use of vitamin D fortified foods and/and dietary supplements to benefit gastrointestinal health. However, intake levels might beneficially be informed by personalized genetic and genomic information, for optimal disease prevention and maintenance of remission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2015
    • "VDBP has other significant functions such as fatty acid transport, the activation of macrophages and the actin scavenging system. Malnutrition may also lower its concentration [61,115116117. Actin is released from cells upon injury, and GC binds actin to clear it from the circulation, thus preventing actin's harmful effects on blood vessels [117]. "
    [Show abstract] [Hide abstract] 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 inter actions with the individual's micro biome. 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. 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.
    Full-text · Article · Aug 2015 · Molecular Nutrition & Food Research
    • "Eloranta et al. (2008) added to this body of work by looking at two single nucleotide polymorphisms of Vitamin D Binding protein (DBP) and found the DBP 420 variant Lys was less frequent in IBD cases compared with controls (allele frequencies, p = 0.034; homozygous carrier genotype frequencies, p = 0.006). Another DBP polymorphism (DBP 416) was not associated with IBD, but the haplotype consisting of 416 Asp and 420 Lys was more frequent in controls, especially when compared to UC patients (Odds ratio, 4.390) [35]. Thus, there are suggestions that genetics does have an influence on vitamin D levels. "
    [Show abstract] [Hide abstract] ABSTRACT: Vitamin D is known to be vital in maintaining bone health, mineralisation and for fracture prevention. It has also been implicated in a number of autoimmune diseases and has therefore been studied for its potential role in Inflammatory Bowel Disease (IBD). This review looks at the current literature on the role of vitamin D and its potential role as an immunomodulator, disease modifier and bone health in IBD patients. There is substantial supporting evidence of an important role from epidemiological, genetic and immunological studies, but there is also conflicting evidence and nothing proving to be definitive from clinical studies. There are also a number of confounders with IBD patients, as their lifestyles and medications may affect vitamin D levels. Murine studies have added vast amounts to our knowledge of vitamin D and its antimicrobial role, as well as its effect on immune cell proliferation other inflammatory molecules, such as Tumour Necrosis Factor-α (TNFα). It is clear that larger trials investigating the effects of oral supplementation of vitamin D in IBD patients are necessary.
    Full-text · Article · Jun 2015
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