Elsevier

The Lancet

Volume 355, Issue 9204, 19 February 2000, Pages 618-621
The Lancet

Early Report
Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study

https://doi.org/10.1016/S0140-6736(99)02301-6Get rights and content

Summary

Background

Susceptibility to disease after infection by Mycobacterium tuberculosis is influenced by environmental and host genetic factors. Vitamin D metabolism leads to activation of macrophages and restricts the intracellular growth of M tuberculosis. This effect may be influenced by polymorphisms at three sites in the vitamin D receptor (VDR) gene. We investigated the interaction between serum vitamin D (25-hydroxycholecalciferol) concentrations and VDR genotype on susceptibility to tuberculosis.

Methods

This study was a hospital-based case-control analysis of Asians of Gujarati origin, a mainly vegetarian immigrant population with a high rate of tuberculosis. We typed three VDR polymorphisms (defined by the presence of restriction endonuclease sites for Taq1, Bsm1, and Fok1) in 91 of 126 untreated patients with tuberculosis and 116 healthy contacts who had been sensitised to tuberculosis. Serum 25-hydroxycholecalciferol was recorded in 42 contacts and 103 patients.

Findings

25-hydroxycholecalciferol deficiency was associated with active tuberculosis (odds ratio 2·9 [95% Cl 1·3–6·5], p=0·008), and undetectable serum 25-hydroxycholecalciferol (<7 nmol/L) carried a higher risk of tuberculosis (9·9 [1·3–76·2], p=0·009). Although there was no significant independent association between VDR genotype and tuberculosis, the combination of genotype TT/Tt and 25-hydroxycholecalciferol deficiency was associated with disease (2·8 [1·2–6·5]) and the presence of genotype ff or undetectable serum 25-hydroxycholecalciferol was strongly associated with disease (5·1 [1·4–18·4]).

Interpretation

25-hydroxycholecalciferol deficiency may contribute to the high occurrence of tuberculosis in this population. Polymorphisms in the VDR gene also contribute to susceptibility when considered in combination with 25-hydroxycholecalciferol deficiency.

Introduction

Susceptibility to disease after infection with Mycobacterium tuberculosis is influenced by environmental and host genetic factors.1, 2 This gene-environment interaction is important because tuberculosis is predicted to be the largest single infectious cause of death between 1990 and 2020.3

Susceptibility to tuberculosis may be increased by deficiency of vitamin D (25-hydroxycholecalciferol).4, 5 The active metabolite of 25-hydroxycholecalciferol, 1,25-dihydroxyvitamin D, helps mononuclear phagocytes to suppress the intracellular growth of M tuberculosis.6, 7 Serum concentrations of 25-hydroxycholecalciferol in tuberculosis patients have been reported to be lower than in healthy controls in some populations,8 but do not differ substantially in others.9 There is an early summer peak in notifications of tuberculosis in the UK, suggesting that low post-winter trough concentrations of 25-hydroxycholecalciferol may contribute to the reactivation of latent infection.10 In addition, vegetarian diet may be a risk factor for tuberculosis in immigrant Asians living in south London.11, 12

Genetic association studies of human tuberculosis have defined a role for HLA-DR2,13 haptoglobin 2-2,14 and variants of the human NRAMP1 gene15 in susceptibility to severe pulmonary tuberculosis. In addition, homozygotes (tt genotype) for a variant of the vitamin D receptor (VDR), which is associated with decreased bone-mineral density,16 are at decreased risk of tuberculosis.17 This VDR polymorphism, detected by the presence or absence of a restriction site for endonuclease Taq1, does not change the sequence of VDR but has been associated with increased VDR mRNA stability.16 A second VDR polymorphism, also associated with decreased bone-mineral density,18, 19 results from a C-to-T transition that creates an alternative initiation codon (ATG) three codons from the downstream start site.20 This polymorphism, which has not been previously investigated in tuberculosis patients, is detected by the presence of a site for the restriction endonuclease Fok1. The VDR encoded by the f allele is increased in length by three aminoacids, and transcription of this allele is 1·7 times less efficient than the F allele.19

There is a very high rate of post-primary tuberculosis among Gujarati Asians living in Harrow, UK. The notification rate is as high as 809 per 100 000 population among those who arrived in the UK within the last 5 years.21 There is an unusual excess of extrapulmonary disease in these individuals and the overall rate is considerably higher than that recorded in their country of origin. However, poverty is not a factor because this immigrant community is generally prosperous. Within this population many marriages are arranged, marriage to non-Gujarati Hindus is rare, and marriage to non-Hindus is very rare. Most members of this community are strict vegetarians, and infants younger than 2 years have lower serum 25-hydroxycholecalciferol concentrations than white infants.22 This community is sufficiently homogenous for genetic study and of special interest to investigate the interaction between VDR polymorphism and acquired 25-hydroxycholecalciferol deficiency on reactivation of M tuberculosis infection.

Section snippets

Participants

126 untreated patients with tuberculosis and 116 healthy tuberculosis contacts who were Hindu, resident in London, and of Gujarati origin were recruited from Northwick Park Hospital, Harrow, UK. 150 (62·0%) participants had been inoculated with BCG vaccine (including 78 untreated patients).

All 126 patients (mean age 45·5 years; 83 women, 43 men) were recruited during 3 years on the basis of their willingness to participate, and tuberculosis infection was confirmed by biopsy or culture. Culture

25-hydroxycholecalciferol concentrations

103 patients and 42 contacts had data available on 25-hydroxycholecalciferol concentration. Median 25-hydroxycholecalciferol concentrations were low in all participants, although significantly lower in tuberculosis patients (table 1). Over half the individuals in both groups had 25-hydroxycholecalciferol concentrations less than 20 nmol/L. 25-hydroxycholecalciferol deficiency (≤10 nmol/L) and undetectable 25-hydroxycholecalciferol concentrations were significantly associated with tuberculosis (

Discussion

There is a high prevalence of 25-hydroxycholecalciferol deficiency in Gujarati Asians living in London, a population in whom the incidence of tuberculosis is also high. The lowest serum 25-hydroxycholecalciferol concentrations were found in patients with active disease, and the greatest risk of tuberculosis (nearly ten-fold higher) was associated with an undetectable 25-hydroxycholecalciferol concentration. Although patients with severe disease showed a trend towards a lower frequency of the tt

References (32)

  • GA Rook et al.

    Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes

    Immunology

    (1986)
  • PD Davies et al.

    Serum concentrations of vitamin D metabolites in untreated tuberculosis

    Thorax

    (1985)
  • A Douglas et al.

    Seasonality of tuberculosis: the reverse of other respiratory diseases in the UK

    Thorax

    (1996)
  • PJ Finch et al.

    Risk of tuberculosis in immigrant Asians: culturally acquired immunodeficiency?

    Thorax

    (1991)
  • DP Strachan et al.

    Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians

    Thorax

    (1995)
  • SP Singh et al.

    Human leukocyte antigen (HLA)-linked control of susceptibility to pulmonary tuberculosis and association with HLA-DR types

    J Infect Dis

    (1983)
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