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MAL adaptor (TIRAP) S180L polymorphism and severity of disease among tuberculosis patients
Rajagopalan Saranathan1, Pattabiraman Sathyamurthi1, Kannan Thiruvengadam2
1Department of HIV/AIDS, National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India.
Objective:
Though several genetic variants have been recognized to be associated with susceptibility to Tuberculosis (TB) infection and disease, a recent observation on the association of TIRAP C975T (S180L) variants with TB disease severity in mice model prompted us to assess their relevance in humans. In addition, TIRAP variants have also been reported to be associated with varied circulating Interferon-gamma induced protein (IP-10) levels. We investigated the association of TIRAP variants with severity of TB disease and IP-10 production in humans, which may be useful in predicting poor clinical outcome.
Methods:
Culture positive symptomatic adult pulmonary TB (PTB) patients enrolled between August 2014 and October 2017 were included in this investigation. Allelic discrimination PCR and conventional IP-10 quantification methods were employed for genotyping and IP-10 measurement followed by statistical investigations to analyse patients' variables.
Results:
Among 211 participants, C/C allele was identified in 70% (n = 147); 26% (n = 55) and 4% (n = 9) had C/T and T/T alleles respectively. There was no significant association between TIRAP variants and smear grade, chest-X-ray score, symptom severity score and circulating IP-10 levels. However, significant association was observed between i) circulating IP-10 levels and time to Mycobacterium Growth Indicator Tube (MGIT) culture conversion (p =0.032); ii) smear grade among active TB patients and circulating IP-10 levels (p =0 .032).
Conclusions:
Although mice experiments showed promising results with more severe disease in C/C and T/T individuals, we did not observe any such association in humans.
Insights
Toll-interleukin 1 receptor domain-containing adapter protein (TIRAP) variants were studied in human tuberculosis (TB) patients. No association was found between TIRAP variants and TB disease severity or Interferon-gamma induced protein (IP-10) levels in humans.
Area of Science:
- Immunogenetics
- Tuberculosis Research
- Host-Pathogen Interactions
Background:
- Genetic variants in Toll-interleukin 1 receptor domain-containing adapter protein (TIRAP) have been linked to disease susceptibility.
- Previous mouse models suggested TIRAP C975T (S180L) variants are associated with Tuberculosis (TB) disease severity and Interferon-gamma induced protein (IP-10) levels.
Purpose of the Study:
- To investigate the association of TIRAP variants with TB disease severity in humans.
- To assess the correlation between TIRAP variants and circulating IP-10 levels in TB patients.
- To determine if TIRAP variants can predict poor clinical outcomes in TB.
Main Methods:
- Genotyping of TIRAP variants using allelic discrimination PCR in 211 culture-positive adult pulmonary TB patients.
- Quantification of circulating IP-10 levels using conventional methods.
- Statistical analysis to correlate TIRAP variants with clinical parameters and IP-10 levels.
Main Results:
- No significant association was found between TIRAP variants and TB disease severity markers (smear grade, chest-X-ray score, symptom severity score).
- Circulating IP-10 levels did not significantly correlate with TIRAP variants.
- Significant associations were observed between IP-10 levels and time to Mycobacterium Growth Indicator Tube (MGIT) culture conversion (p=0.032) and smear grade (p=0.032).
Conclusions:
- Contrary to mouse model findings, human TIRAP variants (C975T) are not associated with TB disease severity or IP-10 levels.
- IP-10 levels show a significant association with TB disease progression markers, suggesting a potential role in clinical outcome prediction.
- Further research is needed to understand the complex interplay of genetic factors and immune responses in human TB.
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