Regulatory Role of Vitamin D Receptor Gene Variants of BsmI, ApaI, TaqI, and FokI Polymorphisms on Macrophage Phagocytosis and Lymphoproliferative Response to Mycobacterium tuberculosis Antigen in Pulmonary Tuberculosis


The regulatory role of vitamin D receptor (VDR) gene variants of BsmI, ApaI, TaqI, and FokI polymorphisms on vitamin D3-modulated macrophage phagocytosis with live Mycobacterium tuberculosis and lymphoproliferative response to M. tuberculosis culture filtrate antigen (CFA) was studied in patients with pulmonary tuberculosis (n = 46) and in normal healthy subjects (NHS) (n = 64). Vitamin D3 at a concentration of 1 × 10−7 M enhanced the phagocytic potential of normal subjects who had a phagocytic index of less than 20%. This increase was seen in subjects with the genotypes BB (p = 0.017), AA (p = 0.016), tt (p = 0.034), and FF (p = 0.013) and the extended genotype BBAAtt (p = 0.034). Normal subjects with BBAAtt performed better phagocytosis than individuals with bbaaTT genotype (p = 0.034). Vitamin D3 at 10−9, 10−8, and 10−7 M concentrations suppressed the lymphoproliferative response to CFA antigen in normal subjects. This decreased lymphocyte response was observed in normal individuals with the genotypes BB (p = 0.0009), tt (p = 0.016), and FF (p = 0.008) and the extended genotype BBAAtt (p = 0.02). Addition of vitamin D3 had no significant effect on macrophage phagocytosis and lymphoproliferative response to CFA in pulmonary TB patients. This may be due to the unresponsive nature of the cells to the action of vitamin D3 or the downregulated VDR expression by virtue of the disease, which renders them inactive. The genotypes BB, tt, and the extended genotype BBAAtt may be associated with increased expression of VDR which in turn regulate the action of vitamin D3 and modulate the immune functions to M. tuberculosis in NHS.

This is a preview of subscription content, access via your institution.


  1. 1.

    Murray CJ, Styblo K, Rouillon A: Tuberculosis in developing countries: Burden, intervention and cost. Bull Int Union Tuberc Lung Dis 65:6–24, 1990

    PubMed  Google Scholar 

  2. 2.

    Hill AV: The genomics and genetics of human infectious disease susceptibility. Annu Rev Genomics Hum Genet 2:373–400, 2001

    PubMed  Google Scholar 

  3. 3.

    Bellamy R: Susceptibility to mycobacterial infections: The impor-tance of host genetics. Genes Immun 4:4–11, 2003

    PubMed  Google Scholar 

  4. 4.

    Dowling GB, Prosser-Thomas EW: Treatment of lupus vulgaris with calciferol. Lancet1:919–922, 1946

    Google Scholar 

  5. 5.

    Davies PD, B rown RC, Church HA, Woodhead JS: The effect of anti-tuberculosis chemotherapy on vitamin D and calcium metabolism. Tubercle 68:261–266, 1987

    PubMed  Google Scholar 

  6. 6.

    Tsoukas CD, Provvedini DM, Manolagas SC: 1,25-dihydroxy vitamin D3: A novel immunoregulatory hormone. Science 224: 1438–1440, 1984

    Google Scholar 

  7. 7.

    Lemire JM, Adams JS, Sakai R, Jordan SC: 1-alpha,25-dihydroxy vitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 74:657–661, 1984

    PubMed  Google Scholar 

  8. 8.

    Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J, Stanford J: Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57:159–163, 1986

    PubMed  Google Scholar 

  9. 9.

    Tokuda N, Levy RB: 1,25-dihydroxy vitamin D3 stimulates phagocytosis but suppresses HLA-DR and CD13 antigen expression in human mononuclear phagocytes. Proc Soc Exp Biol Med 211: 244–250, 1996

    PubMed  Google Scholar 

  10. 10.

    Denis M: Killing of Mycobacterium tuberculosis within human monocytes: Activation by cytokines and calcitriol. Clin Exp Immunol 84:200–206, 1991

    PubMed  Google Scholar 

  11. 11.

    Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D: 1,25-dihydroxy vitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 66:5314–5321, 1998

    PubMed  Google Scholar 

  12. 12.

    Chandra G, Selvaraj P, Jawahar MS, Banurekha VV, Narayanan PR: Effect of vitamin D3 on phagocytic potential of macrophages with live Mycobacterium tuberculosis and lymphoproliferative response in pulmonary tuberculosis. J Clin Immunol 24:249–257, 2004

    PubMed  Google Scholar 

  13. 13.

    Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC: 1,25-dihydroxy vitamin D3 receptors in human leukocytes. Science 221:1181–1183, 1983

    PubMed  Google Scholar 

  14. 14.

    Reichel H, Koeffler HP, Tobler A, Norman AW: 1-alpha,25-dihydroxy vitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 84:3385–3389, 1987

    PubMed  Google Scholar 

  15. 15.

    Malloy PJ, Feldman D: Vitamin D resistance. Am J Med 106: 355–370, 1999

    PubMed  Google Scholar 

  16. 16.

    Morrison NA, Yeoman R, Kelly PJ, Eisman JA: Contribution of trans-acting factor alleles to normal physiological variability: Vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci USA 89:6665–6669, 1992

    PubMed  Google Scholar 

  17. 17.

    Faraco JH, Morrison NA, Baker A, Shine J, Frossard PM: ApaI dimorphism at the human vitamin D receptor gene locus. Nucleic Acids Res 17:2150, 1989

    PubMed  Google Scholar 

  18. 18.

    Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, O'Malley BW: Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 85:3294–3298, 1988

    PubMed  Google Scholar 

  19. 19.

    Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA: Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287, 1994

    Article  PubMed  Google Scholar 

  20. 20.

    Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, Tonai T, Nishisho T, Mori S, Takeda E: A vitamin D receptor gene polymorphism in the translation initiation codon: Effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 12:915–921, 1997

    PubMed  Google Scholar 

  21. 21.

    Eccleshall TR, Garnero P, Gross C, Delmas PD, Feldman D: Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women: The OFELY study. J Bone Miner Res 13:31–35, 1998

    PubMed  Google Scholar 

  22. 22.

    Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV: Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 179:721–724, 1999

    PubMed  Google Scholar 

  23. 23.

    Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN: Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: Acase-control study. Lancet 355:618–621, 2000

    PubMed  Google Scholar 

  24. 24.

    Selvaraj P, Narayanan PR, Reetha AM: Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients & resistance in female contacts. Indian J Med Res 111:172–179, 2000

    PubMed  Google Scholar 

  25. 25.

    Selvaraj P, Chandra G, Kurian SM, Reetha AM, Narayanan PR: Association of vitamin D receptor gene variants of BsmI, ApaI and Fok I polymorphisms with susceptibility or resistance to pulmonary tuberculosis. Curr Sci 84:1564–1568, 2003

    Google Scholar 

  26. 26.

    Nagai S, Wiker HG, Harboe M, Kinomoto M: Isolation and partial characterization of major protein antigens in the culture fluid of Mycobacterium tuberculosis. Infect Immun 59:372–382, 1991

    PubMed  Google Scholar 

  27. 27.

    Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215, 1988

    PubMed  Google Scholar 

  28. 28.

    Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF, Gilsanz V: Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 337:77–82, 1997

    PubMed  Google Scholar 

  29. 29.

    Correa P, Rastad J, Schwarz P, Westin G, Kindmark A, Lundgren E, Akerstrom G, Carling T: The vitamin D receptor (VDR) start codon polymorphism in primary hyperparathyroidism and parathyroid VDR messenger ribonucleic acid levels. J Clin Endocrinol Metab 84:1690–1694, 1999

    PubMed  Google Scholar 

  30. 30.

    Kreutz M, Andreesen R, Krause SW, Szabo A, Ritz E, Reichel H: 1,25-dihydroxy vitamin D3 production and vitamin D3 recep-tor expression are developmentally regulated during differentiation of human monocytes into macrophages. Blood 82:1300–1307, 1993

    PubMed  Google Scholar 

  31. 31.

    Casteels K, Bouillon R, Waer M, Mathieu C: Immunomodulatory effects of 1,25-dihydroxy vitamin D3. Curr Opin Nephrol Hypertens 4:313–318, 1995

    PubMed  Google Scholar 

  32. 32.

    Cadranel J, Hance AJ, Milleron B, Paillard F, Akoun GM, Garabedian M: Vitamin D metabolism in tuberculosis: Production of 1, 25 (OH)2D3 by cells recovered by bronchoalveolar lavage and the role of this metabolite in calcium homeostasis. Am Rev Respir Dis 138:984–989, 1988

    PubMed  Google Scholar 

  33. 33.

    Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ: 1. 25 (OH)2D3 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 85:1588–1593, 1990

    PubMed  Google Scholar 

  34. 34.

    Sharma OP: Hypercalcemia in granulomatous disorders: A clinical review. Curr Opin Pul Med 6:442–447, 2000

    Google Scholar 

  35. 35.

    Beelman CA, Parker R: Degradation of mRNA in eukaryotes. Cell 81:179–183, 1995

    PubMed  Google Scholar 

  36. 36.

    Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh JC, Zitzer H, Tavakkoli P, Galligan MA, Dang HT, Haussler CA, Haussler MR: The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 14: 401–420, 2000

    PubMed  Google Scholar 

  37. 37.

    Whitfield GK, Remus LS, Jurutka PW, Zitzer H, Oza AK, Dang HT, Haussler CA, Galligan MA, Thatcher ML, Encinas Dominguez C, Haussler MR: Functionally relevant polymorphisms in the human nuclear vitamin Dreceptor gene. Mol Cell Endocrinol 177:145–159, 2001

    PubMed  Google Scholar 

  38. 38.

    Colin EM, Weel AE, Uitterlinden AG, Buurman CJ, Birkenhager JC, Pols HA, van Leeuwen JP: Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1,25-dihydroxy vitamin D3. Clin Endocrinol (Oxf) 52:211–216, 2000

    Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Selvaraj, P., Chandra, G., Jawahar, M.S. et al. Regulatory Role of Vitamin D Receptor Gene Variants of BsmI, ApaI, TaqI, and FokI Polymorphisms on Macrophage Phagocytosis and Lymphoproliferative Response to Mycobacterium tuberculosis Antigen in Pulmonary Tuberculosis. J Clin Immunol 24, 523–532 (2004).

Download citation

  • Vit D3
  • VDR gene polymorphism
  • macrophage phagocytosis
  • lymphoproliferation
  • M. tuberculosis antigens
  • pulmonary TB