Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis

<div><p>Background</p><p>The associations between toll-like receptor 2 (TLR2) and toll-like receptor 4(TLR4) polymorphisms and inflammatory bowel disease (IBD) susceptibility remain controversial. A meta-analysis was performed to assess these associations.</p><p>Methods</p><p>A systematic search was performed to identify all relevant studies relating TLR2 and TLR4 polymorphisms and IBD susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by ethnicity and publication quality.</p><p>Results</p><p>Thirty-eight eligible studies, assessing 10970 cases and 7061 controls were included. No TLR2 Arg677Trp polymorphism was found. No significant association was observed between TLR2 Arg753Gln polymorphism and Crohn’s disease (CD) or ulcerative colitis (UC) in all genetic models. Interestingly, TLR4 Asp299Gly polymorphism was significantly associated with increased risk of CD and UC in all genetic models, except for the additive one in CD. In addition, a statistically significant association between TLR4 Asp299Gly polymorphism and IBD was observed among high quality studies evaluating Caucasians, but not Asians. Associations between TLR4 Thr399Ile polymorphisms and CD risk were found only in the allele and dominant models. The TLR4 Thr399Ile polymorphism was associated with UC risk in pooled results as well as subgroup analysis of high quality publications assessing Caucasians, in allele and dominant models.</p><p>Conclusions</p><p>The meta-analysis provides evidence that TLR2 Arg753Gln is not associated with CD and UC susceptibility in Asians; TLR4 Asp299Gly is associated with CD and UC susceptibility in Caucasians, but not Asians. TLR4 Thr399Ile may be associated with IBD susceptibility in Caucasians only. Additional well-powered studies of Asp299Gly and other TLR4 variants are warranted.</p></div

Forest plot showing the association between TLR2 and TLR4 polymorphisms and CD and UC risk.

<p>Squares represent the effect size for the odds ratios of CD or UC risk among subjects. Error bars represent 95% confidence intervals (CI). Diamonds represent pooled estimates within each analysis. (a) TLR2 polymorphisms and CD/UC in dominant model; (b) TLR4 polymorphisms and CD/UC in dominant model.</p

Results of the meta-analysis of the relationship of TLR2 and TLR4 polymorphism with CD or UC risk.

<p>Results of the meta-analysis of the relationship of TLR2 and TLR4 polymorphism with CD or UC risk.</p

Scale for methodologic Quality Assessment of the Single Nucleotide Polymorphism association studies of IBD.

<p>Scale for methodologic Quality Assessment of the Single Nucleotide Polymorphism association studies of IBD.</p

Quality assessment of studies included.

<p>Quality assessment of studies included.</p

Flow chart showing literature search for studies of TLR2 and TLR4 polymorphism in relation to risk of CD and UC.

<p>Flow chart showing literature search for studies of TLR2 and TLR4 polymorphism in relation to risk of CD and UC.</p

Galbraith plot of the association between TLR4 299 polymorphism and UC risk in Caucasians.

<p>Each figure represents a unique article in this meta-analysis. The figures outside the three lines were spotted as the outlier and the possible source of heterogeneity in the analysis pooled from the total available numbers. (a) Galbraith plot results of TLR4 299 polymorphisms and UC risk in the dominant model; (b) Galbraith plot results of TLR4 299 polymorphisms and UC risk in the allele model.</p

Pit patterns and LST subtypes.

<p>P, compared among the four LST subtypes; _ΔP, compared between LST-G-H and LST-NG-F;</p>d<p>, Pearson chi-square test;</p>e<p>, Fisher's exact test.</p

Endoscopic LST imaging and H&E staining of LST tissue specimens.

<p>A, Homogeneous G-type tubular adenoma; B, Flat elevated NG-type hyperplastic polyps; C, Homogeneous G-type serrated adenoma; D, Nodular mixed type tubular villous adenoma with malignancy. E, Pseudo-depressed NG-type villous adenoma with malignancy; Resected tissue specimens were retrieved and immediately fixed in a 10% buffered formalin solution, and subjected to hematoxylin and eosin staining; 200× magnification.</p

Multivariate analysis of LSTs with advanced histology.

<p>D, diameter; TA, tubular adenoma; TVA, tubular villous adenoma; VA, villous adenoma; SA, serrated adenoma; P-colon, proximal colon; D-colon, distal colon.</p