Vitamin D receptor gene polymorphisms and sputum conversion time in pulmonary tuberculosis patients
Introduction
The Western Cape, South Africa had a reported tuberculosis (TB) incidence of 919/100 000 in 2003,1 despite a relatively low HIV prevalence.2 Identification of the genes involved in the response to Mycobacterium tuberculosis (M. tuberculosis) infection may assist in the development of more effective treatment, and a number of genes have been implicated in susceptibility to TB, including Interferon gamma,3 Natural Resistance-Associated Macrophage Protein (NRAMP1 or SLC11A1)4, 5 and Vitamin D Receptor.6, 7, 8, 9
The role of Vitamin D and its receptor (VDR) in innate immunity, and specifically TB, is a subject of intense debate.7, 8, 9, 10, 11 The active metabolite of Vitamin D, 1,25 dihydroxyvitaminD3, suppresses growth of M. tuberculosis in vitro12, 13 and this effect may be facilitated by Toll-Like Receptors in vivo.14 Case-control studies to assess the importance of VDR polymorphisms in TB have produced varying results in different populations.10, 15
Recently Roth et al. (2004) reported an association of VDR polymorphisms with the time to sputum conversion in 78 TB patients,16 although no association with susceptibility to TB was found in a case-control analysis. Validation of this preliminary report of TB treatment response being investigated in relation to a genetic component is vital, preferably in a different population.
We analysed three VDR polymorphisms, FokI, ApaI and TaqI, and a number of other clinical and demographic factors in a large, well characterised group of first time pulmonary TB cases from the population group known as South African Colored in the Western Cape, South Africa. Although admixed, this population has been shown in a previous study not to be stratified.17
The FokI (rs10735810) polymorphism is a functional polymorphism18 and can alter the amount of VDR produced.19, 20ApaI (rs7975232) in intron VIII was analysed because it appears to form an important haplotype.8, 19TaqI (rs731236) is a silent polymorphism (T/C) located in exon IX, in the 3′ region. Strong linkage between the ApaI and TaqI is observed, and they are in linkage disequilibrium (LD) with a polyA variable number of tandem repeats which has been shown to affect transcription.21
A number of variables have been indicated as potentially being involved in the response of TB patients to treatment, and this requires validation. In this study, we have extended the number of variables and examined their effect on response during TB chemotherapy in a large, well-characterised cohort in a South African population.
Section snippets
Patients and surveillance
All TB cases were enrolled for a longitudinal study evaluating pulmonary TB cases during and after treatment.22, 23 Ethical approval for this study was obtained from the Institutional Review Board, Faculty of Health Sciences, Stellenbosch University and from the City of Cape Town. Informed consent was obtained from all subjects. Cases were all first time pulmonary TB patients, not non-tuberculosis mycobacteria or MOTTs infected, HIV negative, 18–65 years old, not pregnant, had no chronic
Case-control study
In the controls, there was strong linkage disequilibrium between ApaI and TaqI (D′=0.999). FokI was not linked with either TaqI or ApaI, (D′=0.048 and 0.005, respectively). All polymorphisms were in Hardy Weinberg equilibrium.
No association was found between genotype or allele counts for the individual VDR polymorphisms and the presence or absence of pulmonary TB (Table 1). A non-significant association was seen between the inferred FokI-ApaI-TaqI haplotype and TB (global p-value=0.078), with
Discussion
Host genetic susceptibility to the development of TB after infection, can be determined via case-control studies comparing genotypes between the groups. More subtle effects of genotype are those impacting on the severity of disease, or the ability of the treated TB cases to recover i.e. undergo sputum conversion to negative culture or smear stain. We investigated both of the above aspects with respect to the VDR gene in a large study of a South African population, as VDR polymorphisms have been
Acknowledgements
We thank the following: The Ravensmead and Uitsig community of the Western Cape, South Africa for their willingness in participating in the project; the nurses in the Desmond Tutu TB Centre, Stellenbosch University for their dedication to the project; Katherine Lawrence for database management; Gillian Black for database input; Nora Carroll and Erica Engelke for bacteriology testing and Robert Gie for evaluating chest radiographs.
Funding: Financial support from GlaxoSmithKline Action TB and a
References (39)
- et al.
Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene
Lancet
(2003) - et al.
Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study
Lancet
(2000) - et al.
Vitamin D receptor gene polymorphisms in relation to vitamin D related disease states
J Steroid Biochem Mol Biol
(2004) - et al.
Score tests for association between traits and haplotypes when linkage phase is ambiguous
Am J Human Genetics
(2002) - et al.
Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43 000 adult male deaths and 35 000 controls
Lancet
(2003) - Incidence of Tuberculosis South Africa Department of Health. Pretoria: Department of Health ....
- National HIV sero-prevelance survey of women attending public antenatla clinics in South Africa 1998. Pretoria:...
- et al.
Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans
N Engl J Med
(1998) - et al.
SLC11A1 (NRAMP1) but not SLC11A2 (NRAMP2) polymorphisms are associated with susceptibility to tuberculosis in a high-incidence community in South Africa
Int J Tuberc Lung Dis
(2004) - et al.
Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene
J Infect Dis
(1999)
Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients & resistance in female contacts
Indian J Med Res
Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study
J Infect Dis
Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk
Int J Tuberc Lung Dis
Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi
Am J Trop Med Hyg
Killing of Mycobacterium tuberculosis within human monocytes: activation by cytokines and calcitriol
Clin Exp Immunol
1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line
Infect Immun
Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response
Science
VDR and NRAMP1 gene polymorphisms in susceptibility to pulmonary tuberculosis among the Chinese Han population: a case-control study
Int J Tuberc Lung Dis
Association between Vitamin D Receptor Gene Polymorphisms and Response to Treatment of Pulmonary Tuberculosis
J Infect Dis
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