Journal Article

DKFZ-2024-00483

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Mandle, H. B. ; Jenab, M. ; Gunter, M. J. ; Tjønneland, A. ; Olsen, A. ; Dahm, C. C. ; Zhang, J. ; Sugier, P.-E. ; Rothwell, J. ; Severi, G. ; Kaaks, R.DKFZ* ; Katzke, V. A.DKFZ* ; Schulze, M. B. ; Masala, G. ; Sieri, S. ; Panico, S. ; Sacerdote, C. ; Bonet, C. ; Sánchez, M.-J. ; Amiano, P. ; Huerta, J. M. ; Guevara, M. ; Palmqvist, R. ; Löwenmark, T. ; Perez-Cornago, A. ; Weiderpass, E. ; Heath, A. K. ; Cross, A. J. ; Vineis, P. ; Hughes, D. J. ; Fedirko, V.

2025
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/mutage/geae008

Abstract: 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.

Keyword(s): colorectal neoplasms ; gut barrier ; incidence ; inflammation ; single nucleotide polymorphism (SNP)

Note: 2025 Mar 15;40(1):48-60

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Contributing Institute(s):

1. Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2024

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; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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