Association between Gc genotype and susceptibility to TB is dependent on vitamin D status

Martineau, Adrian R.; Leandro, Ana C; Anderson, Suzanne T.; Newton, Sandra M.; Wilkinson, Katalin A.; Nicol, Mark P.; Pienaar, Sandra; Skolimowska, Keira; Rocha, M.A.; Rolla, Valéria Cavalcanti; Levin, Michael; Davidson, Robert N.; Bremner, Stephen; Griffiths, Christopher J.; Eley, Brian; Bonecini-Almeida, Maria da Glória; Wilkinson, Robert J.

doi:10.1183/09031936.00087009

Cited by 106 publications

(85 citation statements)

References 27 publications

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“…We have previously reported that vitamin D deficiency is associated with susceptibility to TB in London and that this association is modified by polymorphisms in the vitamin D receptor and vitamin D binding protein (8,9). We have also shown that in vivo vitamin D supplementation enhances immunity to mycobacteria both in healthy people (10) and in a genetically defined subgroup of patients with active TB (11).…”

mentioning

confidence: 87%

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa

Martineau

Nhamoyebonde

Oni

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

183

181

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Vitamin D deficiency is associated with susceptibility to tuberculosis (TB) in HIV-uninfected people in Europe, but it is not known whether such an association exists among HIV-infected people in subtropical Africa. We conducted a cross-sectional study to determine whether vitamin D deficiency was associated with susceptibility to active TB in and HIV-infected (n = 174) black Africans in Cape Town, South Africa. We also investigated whether there was evidence of seasonal variation in vitamin D status and TB notifications in this setting over an 8-y period.nmol/L) was present in 232 (62.7%) of 370 participants and was associated with active TB in both HIV-uninfected (odds ratio = 5.2, 95% confidence interval: 2.8-9.7; P < 0.001) and HIV-infected (odds ratio = 5.6, 95% confidence interval: 2.7-11.6; P < 0.001) people. We have previously reported that vitamin D deficiency is associated with susceptibility to TB in London and that this association is modified by polymorphisms in the vitamin D receptor and vitamin D binding protein (8,9). We have also shown that in vivo vitamin D supplementation enhances immunity to mycobacteria both in healthy people (10) and in a genetically defined subgroup of patients with active TB (11). Reports of seasonal variation in the prevalence of vitamin D deficiency (12) and TB incidence (13) in the United Kingdom provide further evidence that low vitamin D status may compromise antimycobacterial immunity in this setting.The prevalence of profound vitamin D deficiency among TB patients in tropical Africa is much lower than in Europe [reported in 0.3-11.2% of patients with TB in tropical Africa (14-17) vs. 64-84% of patients with TB in ]. The prevalence of vitamin D deficiency in TB patients with and without HIV infection in subtropical Africa has not previously been reported. There is particularly good reason to investigate this question in Cape Town, South Africa, because TB incidence in Cape Town is higher than elsewhere in South Africa (21) and the ability of sunlight to synthesize vitamin D is compromised during the winter in Cape Town (latitude 33°south) but not in Johannesburg (latitude 26°south) (22). We therefore conducted an observational study to determine whether vitamin D deficiency is associated with susceptibility to active TB in HIVinfected and HIV-uninfected adults in Cape Town and to investigate whether there is evidence of seasonal variation in vitamin D status and TB notifications in this setting.

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confidence: 87%

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa

Martineau

Nhamoyebonde

Oni

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

183

181

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“…Since then, eleven case-control studies investigating the association between vitamin D status and susceptibility to active TB have been published. Of these, seven have reported a statistically significant association between vitamin D deficiency and susceptibility to active TB (34)(35)(36)(37)(38)(39)(40) , three have reported a non-statistically significant trend towards such an association (41)(42)(43) and one (44) has reported that active TB was associated with both 'high' and 'low' serum 25(OH)D concentrations (> 140 and < 75 nmol/l, respectively). Potential explanations for an association between vitamin D deficiency and active TB include both causality (i.e.…”

Section: Association Between Vitamin D Deficiency and Susceptibility mentioning

confidence: 99%

Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis

Martineau

2011

Proc. Nutr. Soc.

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Tuberculosis (TB) is a major cause of mortality, responsible for 1 . 68 million deaths worldwide in 2009. The global prevalence of latent Mycobacterium tuberculosis infection is estimated to be 32 %, and this carries a 5-20% lifetime risk of reactivation disease. The emergence of drug-resistant organisms necessitates the development of new agents to enhance the response to antimicrobial therapy for active TB. Vitamin D was used to treat TB in the pre-antibiotic era, and its active metabolite, 1,25-dihydoxyvitamin D, has long been known to enhance the immune response to mycobacteria in vitro. Vitamin D deficiency is common in patients with active TB, and several clinical trials have evaluated the role of adjunctive vitamin D supplementation in its treatment. Results of these studies are conflicting, reflecting variation between studies in baseline vitamin D status of participants, dosing regimens and outcome measures. Vitamin D deficiency is also recognised to be highly prevalent among people with latent M. tuberculosis infection in both high-and low-burden settings, and there is a wealth of observational epidemiological evidence linking vitamin D deficiency with increased risk of reactivation disease. Randomised controlled trials of vitamin D supplementation for the prevention of active TB have yet to be performed, however. The conduct of such trials is a research priority, given the safety and low cost of vitamin D supplementation, and the potentially huge public health consequences of positive results. Tuberculosis: Vitamin D: Immunomodulation: Clinical trialsTuberculosis (TB) is a major public health problem. The global prevalence of latent Mycobacterium tuberculosis (MTB) infection has been estimated at 32% (1) , and this carries a 5-20% lifetime risk of reactivation disease in people who are not infected with HIV (2) ; reactivation rates higher than 10% per annum have been reported in HIVinfected people (3) . The WHO estimates that in 2009 there were 9 . 4 million incident cases of active TB, 14 million prevalent cases of TB, 1 . 3 million deaths from TB in HIV-uninfected people and 0 . 38 million deaths from TB in HIV-infected people (4) . The development of new agents to prevent acquisition or reactivation of latent MTB infection and to allow shortening of antimicrobial therapy regimens for active TB without loss of efficacy is a research priority. This paper reviews the growing body of evidence from studies conducted both in vitro and in vivo suggesting that vitamin D might have a role in the prevention and treatment of TB.

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“…Calcitriol is synthesized by the vitamin D 1-α hydroxylase enzyme, the expression of which is up-regulated in leukocytes and pulmonary epithelium following ligation of Toll-like receptors by pathogen-associated ligands (11,12). Extrarenal generation of calcitriol is dependent on the availability of its precursor calcidiol, the major circulating vitamin D metabolite that supports induction of antimicrobial responses in vitro (11,13) and the concentrations of which are often low in patients with pulmonary infection (14)(15)(16). Vitamin D supplementation elevates circulating calcidiol concentrations, and may therefore enhance response to antimicrobial therapy for respiratory infections.…”

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confidence: 99%

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Coussens

Wilkinson

Hanifa

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

275

204

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Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigenstimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.adjunctive therapy | immunomodulation | antimicrobial peptides | matrix metalloproteinases | steroid hormones

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Association between Gc genotype and susceptibility to TB is dependent on vitamin D status

Cited by 106 publications

References 27 publications

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa

Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

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