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Regulatory Role of Promoter and 3′ UTR Variants of Vitamin D Receptor Gene on Cytokine Response in Pulmonary Tuberculosis

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Abstract

Vitamin D receptor (VDR) gene variants are shown to regulate immune response in tuberculosis. We studied the influence of VDR promoter (Cdx-2 and A1012G), 3′ untranslated region (Apa I, Bsm I, and Taq I) and start codon (Fok I) polymorphisms on 1,25(OH)2D3-modulated IL-12p40, IFN-γ, IL-10, and IL-5 response to live Mycobacterium tuberculosis and its culture filtrate antigen (CFA) in 60 normal healthy subjects and 51 pulmonary tuberculosis patients. In peripheral blood mononuclear cell cultures with CFA and 1,25(OH)2D3, IL-12p40, and IFN-γ levels were significantly decreased (p < 0.05) and IL-10 levels were significantly increased (p < 0.05) in patients with GG genotype. The extended genotype bbaaTT (baT haplotype) was associated with decreased IL-12p40 and IFN-γ levels and significantly increased IL-10 levels (p < 0.05). The Cdx-2 GG genotype and baT haplotype are associated with a suppressed Th1 and increased IL-10 response, which suggests that 1,25(OH)2D3 probably through the VDR polymorphic variants augments the anti-inflammatory response at the site of M. tuberculosis infection.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Selvaraj P, Chandra G, Kurian SM, Reetha AM, Narayanan PR. Association of vitamin D receptor gene variants of Bsm I, Apa I and Fok I polymorphisms with susceptibility or resistance to pulmonary tuberculosis. Curr Sci 2003;84:1564–8.

    CAS  Google Scholar 

  3. 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 2000;111:172–9.

    PubMed  CAS  Google Scholar 

  4. Charpy J. Aspects of vitamin and functional substance therapy in dermatology. Bull Med 1950;64:555–9.

    PubMed  CAS  Google Scholar 

  5. Imazeki I, Matsuzaki J, Tsuji K, Nishimura T. Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity. Biomed Res 2006;27:1–9.

    Article  PubMed  CAS  Google Scholar 

  6. Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995;125:1704S–8S.

    PubMed  CAS  Google Scholar 

  7. Muller K, Odum N, Bendtzen K. 1,25-dihydroxyvitamin D3 selectively reduces interleukin-2 levels and proliferation of human T cell lines in vitro. Immunol Lett 1993;35:177–82.

    Article  PubMed  CAS  Google Scholar 

  8. 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: a case-control study. Lancet 2000;355:618–21.

    Article  PubMed  CAS  Google Scholar 

  9. Arai H, Miyamoto KI, Yoshida M, Yamamoto H, Taketani Y, Morita K, Kubota M, Yoshida S, Ikeda M, Watabe F, Kanemasa Y, Takeda E. The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 2001;16:1256–64.

    Article  PubMed  CAS  Google Scholar 

  10. Halsall JA, Osborne JE, Potter L, Pringle JH, Hutchinson PE. A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibility and prognosis in malignant melanoma. Br J Cancer 2004;91:765–70.

    PubMed  CAS  Google Scholar 

  11. Selvaraj P, Chandra G, Jawahar MS, Rani MV, Rajeshwari DN, Narayanan PR. Regulatory role of vitamin D receptor gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on macrophage phagocytosis and lymphoproliferative response to Mycobacterium tuberculosis antigen in pulmonary tuberculosis. J Clin Immunol 2004;24:523–32.

    Article  PubMed  CAS  Google Scholar 

  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 2004;24:249–57.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. 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 1999;84:1690–4.

    Article  PubMed  CAS  Google Scholar 

  15. 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 1994;367:284–7.

    Article  PubMed  CAS  Google Scholar 

  16. Fang Y, van Meurs JB, Bergink AP, Hofman A, van Duijn CM, van Leeuwen JP, Pols HA, Uitterlinden AG. Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly. J Bone Miner Res 2003;18:1632–41.

    Article  PubMed  CAS  Google Scholar 

  17. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene 2004;338:143–56.

    Article  PubMed  CAS  Google Scholar 

  18. Carling T, Rastad J, Akerstrom G, Westin G. Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors. J Clin Endocrinol Metab 1998;83:2255–9.

    Article  PubMed  CAS  Google Scholar 

  19. Yamagata M, Nakajima S, Tokita A, Sakai N, Yanagihara I, Abuja K, Ozono K. Analysis of the stable levels of messenger RNA derived from different polymorphic alleles in the vitamin D receptor gene. J Bone Miner Metab 1999;17:164–70.

    Article  PubMed  CAS  Google Scholar 

  20. Ogunkolade BW, Boucher BJ, Prahl JM, Bustin SA, Burrin JM, Noonan K, North BV, Mannan N, McDermott MF, DeLuca HF, Hitman GA. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes 2002;51:2294–300.

    Article  PubMed  CAS  Google Scholar 

  21. Uitterlinden AG, Pols HA, Burger H, Huang Q, Van Daele PL, Van Duijn CM, Hofman A, Birkenhager JC, Van Leeuwen JP. A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res 1996;11:1241–8.

    Article  PubMed  CAS  Google Scholar 

  22. Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1, 25(OH)2D2 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 1990;85:1588–93.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We acknowledge the Indian Council of Medical Research and the Council of Scientific and Industrial Research, New Delhi for providing senior research fellowships to Ms. M. Vidyarani (ICMR), Mr. K. Alagarasu (ICMR), and Mr. S. Prabhu Anand (CSIR). We thank Ms. Harini Suryanarayanan, JRF, ICMR, for the technical help rendered by her in this study. We thank the clinicians and staff of Tuberculosis Research Centre (TRC) and the Institute of Thoracic medicine, Chetput, Chennai for their kind assistance in obtaining patient blood samples.

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  1. Department of Immunology, Tuberculosis Research Centre, Indian Council of Medical Research, Mayor V.R. Ramanathan Road, Chetput, Chennai, 600 031, India

    P. Selvaraj, M. Vidyarani, K. Alagarasu, S. Prabhu Anand & P. R. Narayanan

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  1. P. Selvaraj
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  2. M. Vidyarani
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  3. K. Alagarasu
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  4. S. Prabhu Anand
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  5. P. R. Narayanan
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Correspondence to P. Selvaraj.

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Selvaraj, P., Vidyarani, M., Alagarasu, K. et al. Regulatory Role of Promoter and 3′ UTR Variants of Vitamin D Receptor Gene on Cytokine Response in Pulmonary Tuberculosis. J Clin Immunol 28, 306–313 (2008). https://doi.org/10.1007/s10875-007-9152-5

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  • DOI: https://doi.org/10.1007/s10875-007-9152-5

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