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Functional Polymorphism in the NFE2L2 Gene Associated With Tuberculosis Susceptibility.

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Genetic variations in NFE2L2, including the rs13005431 polymorphism, are linked to tuberculosis (TB) susceptibility. Allele C may increase TB risk by reducing NFE2L2 gene activity.

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Area of Science:

  • Genetics and Immunology
  • Molecular Biology
  • Infectious Diseases

Background:

  • Nuclear transcription factor erythroid 2 p45-related factor 2 (Nrf2), encoded by NFE2L2, is crucial for regulating antioxidant gene expression.
  • Investigating the association between NFE2L2 single nucleotide polymorphisms (SNPs) and tuberculosis (TB) susceptibility, including latent TB infection (LTBI), is important for understanding disease mechanisms.

Purpose of the Study:

  • To examine the relationship between NFE2L2 gene polymorphisms and the risk of developing tuberculosis (TB) and latent tuberculosis infection (LTBI).
  • To elucidate the functional mechanisms underlying the association between NFE2L2 SNPs and TB susceptibility.

Main Methods:

  • Genotyping of five tag polymorphisms in the NFE2L2 gene among 1950 unrelated Chinese Han participants across two independent study groups.
  • Functional analysis of the rs13005431 polymorphism using dual-luciferase reporter assays and mRNA expression level comparisons.
  • Statistical analysis to assess associations between NFE2L2 genotypes, haplotypes, and TB/LTBI status, with adjustments for confounding factors.

Main Results:

  • Alleles rs13005431_C and rs2364723_G were significantly associated with increased TB susceptibility (P=0.010 and P=0.041, respectively).
  • Haplotype rs1049751-rs13005431 AC was more frequent in the TB group, while haplotype AT was more common in healthy controls.
  • The rs13005431C allele demonstrated reduced NFE2L2 promoter activity and was associated with decreased NFE2L2 mRNA levels in activated neutrophils, suggesting impaired transcriptional regulation.

Conclusions:

  • The study suggests that the C allele of the NFE2L2 rs13005431 polymorphism may confer increased susceptibility to tuberculosis.
  • This increased susceptibility is potentially mediated by the down-regulation of NFE2L2 transcriptional activity by the rs13005431C allele.