Tumour necrosis factor alpha (-238 and -308) and beta gene polymorphisms in pulmonary tuberculosis : haplotype analysis with HLA-A, B and DR genes.

Selvaraj, P.; Sriram, U.; Mathan Kurian, S.; Reetha, A.M.; Narayanan, P.R.

Tuberculosis; 2001; 81; 335-341.          

Setting : A study of tumour necrosis factor a and b (TNF a and b ) gene polymorphism and haplotype analysis with HLA in pulmonary tuberculosis.

Objective : To determine whether TNF a (-238 and -308) and TNF b ( Nco I polymorphism in intron 2) genes either alone or in combination with human leucocyte antigens (HLA) as haplotypes afford susceptibility or resistance to pulmonary tuberculosis as well as bacteriological relapse of the disease.

Design : Tumour necrosis factor a -238, -308 (TNF a -238, -308) and TNF b ( Nco I) gene polymorphisms were carried out in HLA-A, B and DR typed pulmonary tuberculosis patients ( n=210 ) and 120 normal healthy control subjects.

Results : No difference in the genotype frequencies of TNF a -238 and -308 and TNF b was seen between control subjects and pulmonary tuberculosis patients. Of the HLA-TNF haplotypes analysed, the infrequent allele (A) of TNF a 238 was in strong linkage disequilibrium with HLA-A1 (P corrected: Pc=0.001), B17 (Pc<0.0001) and DR7 (Pc=0.01) in control subjects and with B17 (Pc<0.0001) in pulmonary tuberculosis. The infrequent allele 2 of TNF a -308 and the infrequent allele 2 of TNF b were in strong linkage disequilibrium with HLA-B21. An increased haplotype frequency of HLA-B17-TNF a -238/A ( P =0.05), B17-TNF a 308/2 ( P =0.03) and B17-TNF a 308/2 ( P =0.01) was observed in bacteriological relapse patients than quiescent patients.

Conclusion : The present study suggests that TNF a (-238 and -308) and TNF b gene variants are not associated independently with the susceptibility to pulmonary tuberculosis. However, in combination with the HLA genes/gene products such as HLA-A1, B17, B21 and DR7, the TNF a and b genes as haplotypes are associated with protection against the disease as well as an increased susceptibility to bacteriological relapse.

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