Vitamin D, serum 25(OH)D, LL-37 and polymorphisms in a Canadian First Nation population with endemic tuberculosis
Canadian Aboriginal (indigenous) populations, which include First Nations, Metis and Inuit peoples, suffer from a high burden of morbidity and mortality from both infectious (including tuberculosis (TB), respiratory syncytial virus and influenza) and chronic (including diabetes mellitus and autoimmune) diseases (1–4). Increasing attention to the role of nutrition in the health and disease in Canadian Aboriginal people has led to the recognition of the prevalence of overt hunger as well as the “hidden hunger” of micronutrient deficiency (5–7). Vitamin D insufficiency is common in industrialized and developing nations, and low circulating levels of vitamin D have been associated with a higher risk of infections including active TB (8–10). Low serum vitamin D levels have been reported in First Nation populations as are clinical manifestations of hypovitaminosis D including rickets in children and elevated fracture risk with low mineral bone density in women (5–7,11,12). Risk factors for hypovitaminosis D include northern latitude, food insecurity and poverty. Vitamin D (from food, sunshine and supplements), in particular, has a wide spectrum of activity affecting calcium and bone metabolism, immune and cardiovascular systems, regulation of cell proliferation and glucose metabolism (13).
Like many northern Canadian indigenous communities, the Northlands Denesuline (Dene) First Nation have experienced endemic TB for many years (1,14). Previous studies have demonstrated that the Canadian Dene populations have low winter levels of serum 25-hydroxy vitamin D (25(OH)D) and high vitamin D binding protein (VDBP) (5). We previously demonstrated that vitamin D supplementation resulted in enhanced innate immune responses. In particular, cytokines (interleukin-6, -12 and -23) required to control intracellular pathogens such as Mycobacterium tuberculosis (Mtb) were upregulated in macrophages isolated from Canadian Caucasians in response to a lipoprotein antigen TLR2/1L but not in macrophages from the Dene (15). TLR2/1L is a synthetic lipoprotein of M. tuberculosis, the causative agent of TB. TLR2/1L has been shown to induce the expression of vitamin D receptor (VDR) and the enzyme CYP27B1 required for the synthesis of the active metabolite 1,25(OH)2D of vitamin D (16).
It is currently unclear to what extent, if any, vitamin D levels and metabolism may play in susceptibility/resistance to TB among Dene peoples. Vitamin D metabolites induce the expression of the human antimicrobial host defence peptide, cathelicidin LL-37. The promoter region of the hCAP18 gene, which encodes for LL-37, contains a vitamin D response element (17,18). Induction of LL-37 expression has been shown to be mediated by interaction of VDR and its ligand 1,25(OH)2D, the active form of vitamin D (17). LL-37 is a naturally occurring host defence peptide with both antimicrobial and immunomodulatory properties required for the control of infections, including TB (19,20). Inadequate levels of 25(OH)D suppress the expression of hCAP18/LL-37 and consequently may compromise immune responses to infections (8–10,20). Consistent with this, low plasma levels of LL-37 have been associated with increased susceptibility to infections (21). It is, therefore, possible that impaired immune response to infections may also be due to dysregulation of the vitamin D metabolism pathway and consequently inadequate induction of the peptide LL-37.
Single nucleotide polymorphisms (SNPs) in the genes for VDBP and VDR are associated with altered vitamin D metabolism and impaired immune response to infections (22,23). SNPs at restriction enzyme sites D432E and T436K are known to change the VDBP protein structure resulting in the 3 most common variants of VDBP, Gc1f, Gc1s and Gc2. These variants differentially influence the bioavailability and binding affinity of VDBP to 25(OH)D, thereby affecting vitamin D-mediated induction of the LL-37 (22–25). Similarly, 4 VDR SNPs at restriction enzyme sites, Fok1, Bsm1, Apa1, and Taqα1, have been associated with vitamin D-related disease conditions and susceptibility to infectious diseases (10). Studies linking SNPs of VDBP and VDR to altered immune responses to infections among First Nation populations are limited.
In this prospective study, we examined specific VDBP and VDR SNPs and their correlation with circulating serum levels of vitamin 25(OH)D and LL-37, before and after vitamin D supplementation (1,000 IU/day), in a Dene cohort. Correlations between serum levels of 25(OH)D and LL-37 with VDBP and VDR SNPs may provide insight into factors associated with increased prevalence of TB in the Dene.
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