Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.
Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.
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DOI：
10.1136/gutjnl-2016-311622
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发表时间：
2017-10
期刊：
影响因子：
24.5
通讯作者：
Madeleine MM
中科院分区：
文献类型：
--
作者：
Buas MF;He Q;Johnson LG;Onstad L;Levine DM;Thrift AP;Gharahkhani P;Palles C;Lagergren J;Fitzgerald RC;Ye W;Caldas C;Bird NC;Shaheen NJ;Bernstein L;Gammon MD;Wu AH;Hardie LJ;Pharoah PD;Liu G;Iyer P;Corley DA;Risch HA;Chow WH;Prenen H;Chegwidden L;Love S;Attwood S;Moayyedi P;MacDonald D;Harrison R;Watson P;Barr H;deCaestecker J;Tomlinson I;Jankowski J;Whiteman DC;MacGregor S;Vaughan TL;Madeleine MM
近几十年来，食管腺癌（EA）的发病率在西方国家急剧上升。局部和全身炎症，疾病相关的暴露下游操作，被认为是一个重要的贡献者EA发病机制。已经确定了EA及其前体Barrett食管（BE）的几个风险因素，包括有症状的反流，肥胖和吸烟。遗传易感性的作用仍然是一个积极的研究领域。为了探索与炎症过程相关的生殖系变异是否影响BE/EA的易感性，我们使用了来自2，515例EA病例，3，295例BE病例和3，207例对照的全基因组关联研究（GWAS）的数据。我们的分析包括449个基因的7,863个单核苷酸多态性（SNP），这些基因被分配到五个途径：环氧合酶（考克斯）、细胞因子信号传导、氧化应激、人类白细胞抗原和NFκB。一个基于主成分的分析框架，以评估路径水平和基因水平与疾病风险的关联。我们发现考克斯通路与BE风险相关的显著信号（P=0.0059，FDR q=0.03），在基因水平分析中发现与MGST 1（微粒体谷胱甘肽-S-转移酶1; P=0.0005，q=0.005）相关。对36个MGST 1 SNPs的评估鉴定出14个与BE风险升高相关的变异（q<0.05）。其中，4例随后在一项包括1,851例BE病例和3,496例对照的独立集的荟萃分析中得到证实（P<5.5 × 10−5）。其中三个SNP（rs3852575，rs73112090，rs 4149204）与EA风险的相似升高相关。这项研究提供了与BE/EA风险相关的炎症相关生殖细胞变异的最全面评估，并表明MGST 1的变异影响疾病易感性。
Esophageal adenocarcinoma (EA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation, operating downstream of disease-associated exposures, is considered an important contributor to EA pathogenesis. Several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including symptomatic reflux, obesity, and smoking. The role of inherited genetic susceptibility remains an area of active investigation. To explore whether germline variation related to inflammatory processes influences susceptibility to BE/EA, we used data from a genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls. Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative stress, human leukocyte antigen, and NFκB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (P=0.0059, FDR q=0.03), and in gene-level analyses found an association with MGST1 (microsomal glutathione-S-transferase 1; P=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Of these, four were subsequently confirmed (P<5.5 × 10−5) in a meta-analysis encompassing an independent set of 1,851 BE cases and 3,496 controls. Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar elevations in EA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/EA, and suggests that variants in MGST1 influence disease susceptibility.