Gut barrier dysfunction and related
inflammation are known to be associated with the development and progression of
colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to
endotoxins/
lipopolysaccharide (LPS) sensing and tolerance,
mucin synthesis,
inflammation, and
Crohn's disease with colon and
rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into
Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and
inflammation biomarkers (
flagellin/LPS-specific
immunoglobulins and
C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum
biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and
mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to
inflammation or
Crohn's disease. TLR4 was associated with
colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with
rectal cancer but not
colon cancer. Similarly,
IL10 was associated with
rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not
colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and
inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial
endotoxemia and CRC development.