Missense mutation 1234C>T of TOLL-like receptor 3 gene in ulcerative colitis

Maintenance of intestinal homeostasis suggests dynamic interaction between the host immune system and local microbiota. Impaired immune response, genetic predisposition and changes in microbiota composition lead to chronic gut inflammation, which is the basis for the development of immune pathology accompanying inflammatory bowel disease (IBD). Resident enteric viruses also have immunomodulatory effects in IBD. Toll-like receptors recognizing PAMPs penetrating intestinal barrier are an important component of the inflammatory process in ulcerative colitis (UC). Viral double-stranded RNA is recognized by endosomal TLR3. Our goal was to identify the association between alleles, genotypes of the TLR3 gene and its haplotypes formed with TLR2 genes, TLR1, TLR6, and UC in Russian population of the Chelyabinsk Region. The study groups included 96 patients with UC and 86 healthy individuals. DNA was isolated from whole blood using a column method, polymorphic gene regions were amplified using allele-specific PCR and RFLP, amplification products were detected by gel electrophoresis in a 3% agarose with UV-visualization. The SNP 1234C>T (Leu412Phe) of the TLR3 gene were typed. Linkage disequilibrium parameters were evaluated for the mentioned TLR3 SNP and other SNPs, i.e., 1805T>G (Ser602Ile) in TLR1 gene, 2258G>A (Arg753Gln) in TLR2 gene, 745C>T (Ser249Pro) in TLR6 gene. The frequency analysis of alleles and genotypes of TLR3 SNP 1234C>T showed a statistically significant increase of the mutant T allele frequency (p = 0.019; OR = 1.72; 95% CI: 1.09-2.71), and higher frequency of homozygous TT genotype among the patients with UC (p = 0.011; OR = 4.72; 95% CI: 1.31-17.05). By assessing the parameters of linkage disequilibrium, two haplotypes were discovered that may be predisposition factors for UC, i.e., haplotype 1234*T ~ 2258*A, with linkage of mutant alleles of SNPs 1234C>T TLR3 and 2258G>A TLR2 (p = 0.006; OR = 12.42; 95% CI: 1.61-95.97), as well as haplotype 1234*T ~ 1805*T, with linkage of the mutant allele of SNP 1234C>T TLR3 to wild allele of SNP 1805T>G TLR1 (p = 0.009; OR = 2.94; 95% CI: 1.35-6.42).