Regulatory role of 1, 25-dihydroxyvitamin D3 and vitamin D receptor gene variants on intracellular granzyme A expression in pulmonary tuberculosis.

ABSTRACT

Vitamin D receptor (VDR) genotypes have been shown to be associated with differential susceptibility or resistance to tuberculosis. The influence of FokI, BsmI, ApaI and TaqI variants of VDR gene on 1, 25(OH)(2) D(3) modulated granzyme A expression of cytotoxic lymphocytes induced by culture filtrate antigen (CFA) of Mycobacterium tuberculosis was studied in 40 pulmonary tuberculosis (PTB) patients and 49 normal healthy subjects (NHS) by flow cytometry. In both the study groups, addition of 1, 25(OH)(2) D(3) (10(-7)M) significantly reduced the percentage of granzyme A positive cells in both unstimulated (NHS, p<0.0001; PTB, p=0.02) and stimulated culture conditions (CFA, NHS, p<0.0001; PTB, p=0.0001) which correlated positively with the IFN-gamma levels (unstimulated, p=0.01; CFA stimulated, p=0.004) in NHS. The ApaI aa genotype and bbaaTT extended genotype were associated with a significantly decreased percentage of granzyme A positive cells in NHS (p<0.05). Our results suggest that 1, 25(OH)(2) D(3) suppresses granzyme A probably by down-regulating Th1 cytokine response. Moreover, the VDR gene variants might regulate cytotoxic T-cell response via 1, 25(OH)(2) D(3) mediated suppression of granzyme A expression in tuberculosis.