Association of TLR4 (D299G, T399I), TLR9 -1486T>C, TIRAP S180L and TNF-α promoter (-1031, -863, -857) polymorphisms with risk for systemic lupus erythematosus among South Indians.

The rationale of this case-control study was to explore the association of Toll-like receptor 4 (TLR4) D299G, TLR4 T399I, TLR9 -1486 T>C, TIR-domain-containing adaptor protein (TIRAP) S180 L and tumor necrosis-α (TNF-α) promoter polymorphisms with susceptibility and phenotypic heterogeneity of systemic lupus erythematosus (SLE). PCR-RFLP, real-time PCR was used for the genetic analysis and expression studies and ELISA was used for the determination of specific autoantibodies. TLR4 D299G was associated with the risk for SLE (OR: 1.57, 95% CI: 1.08-2.28), while the TNF-α (-1031, -863, -857) CCC haplotype conferred protection. TLR4 and TIRAP polymorphisms were associated with reduced expression of HLA-DR. The presence of TLR4 and TLR9 polymorphisms increases the MHC2TA expression, while TIRAP polymorphism was associated with reduced expression. TLR4 D299 G showed an inverse association with pulmonary hypertension. TLR 4 T399I and TLR9 -1486 T>C showed a positive association with seizures and photosensitivity, respectively. TIRAP S180 L showed a positive association with alopecia and malar rashes, while an inverse association with psychosis was observed. TLR4 T399I (r = 0.14, p = 0.05) and TIRAP S180 L (r = 0.15, p = 0.03) showed a positive association with anti-Ro antibodies. On the other hand, TLR9 -1486 T>C showed an inverse association with anti-La antibodies (r = -0.20, p = 0.006). To conclude, TLR4 D299G increases the risk for SLE, while TNF-α CCC haplotype reduces the risk for SLE. All these polymorphisms contribute toward phenotypic heterogeneity. TLR4 T399I, TLR9 -1486 T>C and TIRAP S180 L influence specific autoantibody production in SLE.