PT - JOURNAL ARTICLE AU - Matthew F Buas AU - Qianchuan He AU - Lisa G Johnson AU - Lynn Onstad AU - David M Levine AU - Aaron P Thrift AU - Puya Gharahkhani AU - Claire Palles AU - Jesper Lagergren AU - Rebecca C Fitzgerald AU - Weimin Ye AU - Carlos Caldas AU - Nigel C Bird AU - Nicholas J Shaheen AU - Leslie Bernstein AU - Marilie D Gammon AU - Anna H Wu AU - Laura J Hardie AU - Paul D Pharoah AU - Geoffrey Liu AU - Prassad Iyer AU - Douglas A Corley AU - Harvey A Risch AU - Wong-Ho Chow AU - Hans Prenen AU - Laura Chegwidden AU - Sharon Love AU - Stephen Attwood AU - Paul Moayyedi AU - David MacDonald AU - Rebecca Harrison AU - Peter Watson AU - Hugh Barr AU - John deCaestecker AU - Ian Tomlinson AU - Janusz Jankowski AU - David C Whiteman AU - Stuart MacGregor AU - Thomas L Vaughan AU - Margaret M Madeleine TI - Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma AID - 10.1136/gutjnl-2016-311622 DP - 2017 Oct 01 TA - Gut PG - 1739--1747 VI - 66 IP - 10 4099 - http://gut.bmj.com/content/66/10/1739.short 4100 - http://gut.bmj.com/content/66/10/1739.full SO - Gut2017 Oct 01; 66 AB - Objective Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA.Design We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk.Results We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk.Conclusions This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.