Elsevier

Tuberculosis

Volume 87, Issue 4, July 2007, Pages 295-302
Tuberculosis

Vitamin D receptor gene polymorphisms and sputum conversion time in pulmonary tuberculosis patients

https://doi.org/10.1016/j.tube.2007.03.001Get rights and content

Summary

A cohort of pulmonary tuberculosis (TB) patients in a South African admixed population was investigated to determine if the vitamin D receptor gene (VDR) polymorphisms FokI, ApaI, and TaqI are associated with TB susceptibility or time to sputum conversion, and to investigate other clinical and demographic factors affecting the rate of response to treatment. Firstly, a case-control association study of 249 TB cases and 352 healthy controls was carried out to investigate association of VDR polymorphisms with TB susceptibility. Secondly, a cohort of pulmonary tuberculosis patients with conversion times for both sputum smear (n=220) and culture (n=222) were analysed to determine factors contributing to mycobacterial resolution in sputum. Age and gender adjusted Cox regression models were constructed. Our results indicate that the extent of disease at diagnosis was predictive of both smear and culture conversion times in the final models. Smoking status and VDR genotype contributed independently to smear conversion time, with ApaI ‘AA’ genotype and TaqI ‘T’-containing genotypes predictive of a faster response to TB chemotherapy. We did not find an association between VDR genotype and TB in the case-control study. We conclude that the time taken for an individual to convert to sputum negativity while on antituberculosis therapy can be independently predicted by the VDR genotype.

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

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