Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

IF 2.5 4区 医学 Q3 GENETICS & HEREDITY
Mutagenesis Pub Date : 2024-03-05 DOI:10.1093/mutage/geae008
Hannah B Mandle, Mazda Jenab, Marc J Gunter, Anne Tjønneland, Anja Olsen, Christina C Dahm, Jie Zhang, Pierre-Emmanuel Sugier, Joseph Rothwell, Gianluca Severi, Rudolf Kaaks, Verena A Katzke, Matthias B Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Carlotta Sacerdote, Catalina Bonet, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Marcela Guevara, Richard Palmqvist, Thyra Löwenmark, Aurora Perez-Cornago, Elisabete Weiderpass, Alicia K Heath, Amanda J Cross, Paolo Vineis, David J Hughes, Veronika Fedirko
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引用次数: 0

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.

西欧人群中与炎症和肠道屏障功能相关的基因与结直肠癌风险。
众所周知,肠道屏障功能障碍和相关炎症与结直肠癌(CRC)的发生和发展有关。我们研究了与内毒素/脂多糖(LPS)感应和耐受、粘蛋白合成、炎症和克罗恩病有关的 27 个基因中的 292 个单核苷酸多态性(SNPs)与结肠癌和直肠癌风险的关系。结肠癌病例(1374 例;结肠癌 871 例,直肠癌 503 例)与欧洲癌症和营养前瞻性调查队列中的对照组进行了 1:1 匹配。一部分参与者(Ncases=1,001;Ncontrols=667)的血清中含有之前测定的肠道屏障功能和炎症生物标志物(鞭毛蛋白/LPS特异性免疫球蛋白和C反应蛋白[CRP])。在对照组中,19 个不同基因的 42 个独特 SNP 与血清生物标志物的相关性经 Punadjusted 调整后≤0.05。在与肠道渗透性评分相关的 SNPs 中,24 个 SNPs 位于与 LPS 感知和粘蛋白合成相关的基因中。与 CRP 相关的 12 个 SNP 中,有 9 个位于与炎症或克罗恩病相关的基因中。在 SNP 水平(9 个 SNP,均经 Punadjusted 调整后≤0.04)和基因水平(经 Punadjusted 调整后≤0.01)上,TLR4 与结肠癌相关。TLR4 rs10759934 与直肠癌相关,但与结肠癌无关。同样,IL10 在 SNP 和基因水平上与直肠癌风险相关(Punadjusted 均≤0.01),但与结肠癌无关。基因和 SNP 是先验选择的,因此我们提供的是未经调整的 P 值。不过,经过多重检验校正后,没有任何关联具有统计学意义。这项大型综合研究确定了欧洲人群中可能导致结肠癌风险的肠道屏障功能和炎症相关基因,并与宿主遗传背景、肠道屏障通透性、微生物内毒素血症和结肠癌发病之间的潜在病因学联系相一致。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Mutagenesis
Mutagenesis 生物-毒理学
CiteScore
5.90
自引率
3.70%
发文量
22
审稿时长
6-12 weeks
期刊介绍: Mutagenesis is an international multi-disciplinary journal designed to bring together research aimed at the identification, characterization and elucidation of the mechanisms of action of physical, chemical and biological agents capable of producing genetic change in living organisms and the study of the consequences of such changes.
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