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TLR4 D299G polymorphism modulates cytokine expression in ulcerative colitis.

Naresh K Meena1, Ravi Verma, Nirmal Verma

  • 1*School of Life Sciences, Jawaharlal Nehru University †Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.

Journal of Clinical Gastroenterology
|March 9, 2013
PubMed
Summary

Single nucleotide polymorphisms (SNPs) in the Toll-like receptor 4 (TLR4) gene are associated with inflammatory bowel disease (IBD) in North India. These TLR4 gene variations influence cytokine expression in ulcerative colitis (UC).

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Area of Science:

  • Immunogenetics
  • Gastroenterology
  • Molecular Biology

Background:

  • Toll-like receptor 4 (TLR4) is a cell surface receptor crucial for innate immunity, recognizing lipopolysaccharide and activating immune responses.
  • Genetic variations, specifically single nucleotide polymorphisms (SNPs) in the TLR4 gene, have been linked to inflammatory bowel disease (IBD).
  • The influence of these TLR4 gene SNPs on IBD susceptibility can be ethnicity-dependent.

Purpose of the Study:

  • To investigate the association between SNPs in the TLR4 gene and inflammatory bowel disease (IBD) in a North Indian population.
  • To explore how these TLR4 gene SNPs affect the mRNA expression levels of key cytokines in ulcerative colitis (UC) biopsies.

Main Methods:

  • Genotyping of two TLR4 polymorphisms (D299G and T399I) using PCR-RFLP in 199 UC patients, 46 Crohn's disease (CD) patients, and 201 healthy controls.
  • Quantification of inflammatory cytokine mRNA expression (TLR4, TNF-α, IFN-γ, IL-17, IL-23, IL-10) in UC biopsies via RT-PCR.
  • Statistical analysis including Pearson χ test, Fisher exact test, Student t test, and ANOVA for genotype and allele frequencies, and cytokine expression.

Main Results:

  • The TLR4 D299G variant showed significant association with both UC (P=0.009) and CD (P=0.039).
  • The T399I variant was significantly associated with UC (P=0.006) but not CD.
  • UC patients exhibited elevated mRNA levels of TLR4, TNF-α, IFN-γ, IL-17, IL-23, and IL-10 compared to controls. Notably, specific genotypes of D299G (AG and GG) were linked to decreased expression of several inflammatory cytokines, including TLR4, TNF-α, IL-17, and IL-23, and IFN-γ.

Conclusions:

  • TLR4 gene polymorphisms are significantly associated with inflammatory bowel disease in the North Indian population.
  • These genetic variations play a role in modulating the transcription of inflammatory cytokines during UC.
  • The observed modulation of cytokine transcription contributes to aberrant immune responses in ulcerative colitis.