- Email: [email protected]
Vitamin D deficiency and tuberculosis
CORRESPONDENCE
error, these individuals should be excluded from the data analysis.
interpreted as providing support for the hypothesis.
Lars C Stene
Ian R Reid
Section of Epidemiology, National Institute of Public Health, PO Box 4404 Torshov, N-0403 Oslo, Norway
Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand (e-mail: [email protected])
1
2
3
Wilkinson RJ, Llewelyn M, Toossi Z, 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; 355: 618–21. Kleinbaum DG, Kupper L, Morgenstern H. Interaction, effect modification, and syndergism. In: Kleinbaum DG, Kupper L, Morgenstern H, eds. Epidemiologic research: principles and quantitative methods. New York: Wiley & Sons, 1982: 403–18. Greenland S, Rothman KJ. Concepts of interaction. In: Rothman KJ, Greenland S, eds. Modern epidemiology, second edn. Philadelphia: Lippincott-Raven publishers, 1998: 329–42.
Sir—Robert Wilkinson and colleagues1 simply describe an association between serum concentrations of 25-hydroxyvitamin D in Gujarati patients with tuberculosis and they conclude that vitamin D deficiency “may account for a proportion of the acquired susceptibility of Gujarati immigrants to tuberculosis”. They conclude with the suggestion that vitamin D supplementation may have a role in tuberculosis prevention. This study is potentially confounded by the striking dependence of serum 25-hydroxyvitamin D levels on sunlight exposure and by the near certainty that individuals requiring admission to hospital with tuberculosis will have had less sunlight exposure in previous months than the noninfected control subjects studied. Several publications have documented hypovitaminosis D in patients with a variety of conditions requiring admission to hospital,2,3 and in individuals who are seldom outdoors because of frailty.4 It should also be noted that lower concentrations of serum 25-hydroxyvitamin D, are frequently found in individuals from the Indian subcontinent than in Europeans.5 On the basis of the evidence presented by Wilkinson and colleagues, there is no reason to conclude that tuberculosis is associated with any greater degree of vitamin D deficiency than other illnesses producing comparable debility. The laboratory data cited in their paper provide the basis for an interesting hypothesis, but since these changes in serum vitamin D concentrations would be predicted on the basis of the basic principles of vitamin D metabolism, they cannot be
74
1
2
3
4
5
Wilkinson RJ, Llewelyn M, Toossi Z, 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; 355: 618–21. Thomas MK, Lloydjones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338: 777–83. Sato Y, Kikuyama M, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in Parkinsons-disease. Neurology 1997; 49: 1273–78. Gloth FM, Gundberg CM, Hollis BW, Haddad JG, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995; 274: 1683–86. Awumey EMK, Mitra DA, Hollis BW, Kumar R, Bell NH. Vitamin D metabolism is altered in Asian Indians in the southern United States—a clinical research center study. J Clin Endocrinol Metab 1998; 83: 169–73.
according to their genotype, and the odds ratio (OR) for the association between vitamin D deficiency and the risk of tuberculosis calculated separately for each genotype (ORnon-tt and ORtt). Evidence for interaction would require, at the very least, that these two odds ratios were significantly different from each other. Unfortunately, Wilkinson and colleagues did not present their data in a way that permits the appropriate calculations to be carried out. *Amy Berrington, Jane Green, Robert Newton ICRF Cancer Epidemiology Unit, Gibson Building, The Radcliffe Infirmary, Oxford OX2 6HE, UK (e-mail: [email protected]) 1
2
3
Sir—According to Richard Bellamy in his commentary,1 Robert Wilkinson and colleagues2 showed an interaction between vitamin D deficiency and both of the vitamin D receptor polymorphisms under investigaton. Although in table 3 they showed a significantly increased risk of tuberculosis in several small subgroups (eg, in participants with the non-tt genotype and vitamin D deficiency, compared with all other participants) this itself is not a test for interaction. Evidence for an interaction between an environmental exposure (such as vitamin D deficiency) and a genotype would require that the association between the exposure of interest and disease risk in those with a certain genotype was significantly different from the exposure–disease association in those with another genotype.3 A simple method of presenting the data to look for evidence of a geneenvironment interaction in the study by Wilkinson and colleagues is shown in the table. The participants are split Genotype Non-tt
tt
Vitamin D Vitamin D Vitamin D Vitamin D deficient nondeficient nondeficient deficient Tuberculosis a patients Healthy c contacts
b
e
f
d
g
h
ORnon-tt=ad/bc
ORtt=eh/fg
Data presentation for investigation of gene-environment interaction in tuberculosis
Bellamy R. Evidence of gene-environment interaction in development of tuberculosis. Lancet 2000; 355: 588–89. Wilkinson RJ, Llewelyn M, Toossi Z, 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; 355: 618–21. Greenland S, Rothman KJ. Concepts of interaction. In: Greenland S, Rothman KJ, eds. Modern epidemiology, 2nd edn. Philadelphia: Lippincott-Raven; 1998: 329–42.
Authors’ reply Sir—Undetectable 25-hydroxy vitamin D concentrations reflected the lower limit of sensitivity (5–7 nmol/L) of the assay in use and do not therefore constitute an error. Only one healthy contact had an undetectable concentration. Lars Stene makes the point that the analysis of complex traits often necessitates statistical modelling, and Amy Berrington and colleagues suggest a simpler alternative. We did not do this because the preliminary nature of the study meant that it was of insufficient power to confirm a moderate protective effect of the t allele. As stated in the text, there was also no independent association between 25-hydroxy vitamin D deficiency and severity. There was a non-significant trend linking the nontt genotype to severity (table 2). In table 3 the combination non-tt and deficient accounted for 52% of patients with severe disease by comparison with 24% healthy contacts (x2 for linear trend 0·0146), which indicated that these two factors do act synergistically. Alternatively, taking the genotype TT and 25-hydroxy vitamin D deficiency as predisposing factors for severe disease and carrying out the analysis suggested by Berrington and colleageas yields an ORtt of 4 and ORnon-tt of 2·8, again
THE LANCET • Vol 356 • July 1, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
error, these individuals should be excluded from the data analysis.
interpreted as providing support for the hypothesis.
Lars C Stene
Ian R Reid
Section of Epidemiology, National Institute of Public Health, PO Box 4404 Torshov, N-0403 Oslo, Norway
Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand (e-mail: [email protected])
1
2
3
Wilkinson RJ, Llewelyn M, Toossi Z, 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; 355: 618–21. Kleinbaum DG, Kupper L, Morgenstern H. Interaction, effect modification, and syndergism. In: Kleinbaum DG, Kupper L, Morgenstern H, eds. Epidemiologic research: principles and quantitative methods. New York: Wiley & Sons, 1982: 403–18. Greenland S, Rothman KJ. Concepts of interaction. In: Rothman KJ, Greenland S, eds. Modern epidemiology, second edn. Philadelphia: Lippincott-Raven publishers, 1998: 329–42.
Sir—Robert Wilkinson and colleagues1 simply describe an association between serum concentrations of 25-hydroxyvitamin D in Gujarati patients with tuberculosis and they conclude that vitamin D deficiency “may account for a proportion of the acquired susceptibility of Gujarati immigrants to tuberculosis”. They conclude with the suggestion that vitamin D supplementation may have a role in tuberculosis prevention. This study is potentially confounded by the striking dependence of serum 25-hydroxyvitamin D levels on sunlight exposure and by the near certainty that individuals requiring admission to hospital with tuberculosis will have had less sunlight exposure in previous months than the noninfected control subjects studied. Several publications have documented hypovitaminosis D in patients with a variety of conditions requiring admission to hospital,2,3 and in individuals who are seldom outdoors because of frailty.4 It should also be noted that lower concentrations of serum 25-hydroxyvitamin D, are frequently found in individuals from the Indian subcontinent than in Europeans.5 On the basis of the evidence presented by Wilkinson and colleagues, there is no reason to conclude that tuberculosis is associated with any greater degree of vitamin D deficiency than other illnesses producing comparable debility. The laboratory data cited in their paper provide the basis for an interesting hypothesis, but since these changes in serum vitamin D concentrations would be predicted on the basis of the basic principles of vitamin D metabolism, they cannot be
74
1
2
3
4
5
Wilkinson RJ, Llewelyn M, Toossi Z, 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; 355: 618–21. Thomas MK, Lloydjones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338: 777–83. Sato Y, Kikuyama M, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in Parkinsons-disease. Neurology 1997; 49: 1273–78. Gloth FM, Gundberg CM, Hollis BW, Haddad JG, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995; 274: 1683–86. Awumey EMK, Mitra DA, Hollis BW, Kumar R, Bell NH. Vitamin D metabolism is altered in Asian Indians in the southern United States—a clinical research center study. J Clin Endocrinol Metab 1998; 83: 169–73.
according to their genotype, and the odds ratio (OR) for the association between vitamin D deficiency and the risk of tuberculosis calculated separately for each genotype (ORnon-tt and ORtt). Evidence for interaction would require, at the very least, that these two odds ratios were significantly different from each other. Unfortunately, Wilkinson and colleagues did not present their data in a way that permits the appropriate calculations to be carried out. *Amy Berrington, Jane Green, Robert Newton ICRF Cancer Epidemiology Unit, Gibson Building, The Radcliffe Infirmary, Oxford OX2 6HE, UK (e-mail: [email protected]) 1
2
3
Sir—According to Richard Bellamy in his commentary,1 Robert Wilkinson and colleagues2 showed an interaction between vitamin D deficiency and both of the vitamin D receptor polymorphisms under investigaton. Although in table 3 they showed a significantly increased risk of tuberculosis in several small subgroups (eg, in participants with the non-tt genotype and vitamin D deficiency, compared with all other participants) this itself is not a test for interaction. Evidence for an interaction between an environmental exposure (such as vitamin D deficiency) and a genotype would require that the association between the exposure of interest and disease risk in those with a certain genotype was significantly different from the exposure–disease association in those with another genotype.3 A simple method of presenting the data to look for evidence of a geneenvironment interaction in the study by Wilkinson and colleagues is shown in the table. The participants are split Genotype Non-tt
tt
Vitamin D Vitamin D Vitamin D Vitamin D deficient nondeficient nondeficient deficient Tuberculosis a patients Healthy c contacts
b
e
f
d
g
h
ORnon-tt=ad/bc
ORtt=eh/fg
Data presentation for investigation of gene-environment interaction in tuberculosis
Bellamy R. Evidence of gene-environment interaction in development of tuberculosis. Lancet 2000; 355: 588–89. Wilkinson RJ, Llewelyn M, Toossi Z, 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; 355: 618–21. Greenland S, Rothman KJ. Concepts of interaction. In: Greenland S, Rothman KJ, eds. Modern epidemiology, 2nd edn. Philadelphia: Lippincott-Raven; 1998: 329–42.
Authors’ reply Sir—Undetectable 25-hydroxy vitamin D concentrations reflected the lower limit of sensitivity (5–7 nmol/L) of the assay in use and do not therefore constitute an error. Only one healthy contact had an undetectable concentration. Lars Stene makes the point that the analysis of complex traits often necessitates statistical modelling, and Amy Berrington and colleagues suggest a simpler alternative. We did not do this because the preliminary nature of the study meant that it was of insufficient power to confirm a moderate protective effect of the t allele. As stated in the text, there was also no independent association between 25-hydroxy vitamin D deficiency and severity. There was a non-significant trend linking the nontt genotype to severity (table 2). In table 3 the combination non-tt and deficient accounted for 52% of patients with severe disease by comparison with 24% healthy contacts (x2 for linear trend 0·0146), which indicated that these two factors do act synergistically. Alternatively, taking the genotype TT and 25-hydroxy vitamin D deficiency as predisposing factors for severe disease and carrying out the analysis suggested by Berrington and colleageas yields an ORtt of 4 and ORnon-tt of 2·8, again
THE LANCET • Vol 356 • July 1, 2000
For personal use only. Not to be reproduced without permission of The Lancet.