Journal
GUT
Volume 66, Issue 10, Pages 1739-1747Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2016-311622
Keywords
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Categories
Funding
- National Institutes of Health [R21DK099804, R01CA136725]
- Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project [C548/A5675]
- Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project [MGAG1G7R]
- Cancer Research UK (AspECT) [C548/A4584, D9612L00090]
- Histological AssessmeNt Determining EpitheliaL Response (HANDEL) [C548/A9085]
- AstraZeneca UK educational grant
- University Hospitals of Leicester R and D grant
- AspECT [T91 5211, HDRMJQ0]
- BEACON GWAS
- BEACON
- Cancer Research UK [16895, 16942] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10124] Funding Source: researchfish
- Medical Research Council [MC_UU_12022/2] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10090, NF-SI-0611-10154] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10119] Funding Source: researchfish
- MRC [MC_UU_12022/2] Funding Source: UKRI
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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-.B. 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<5.5x10(-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.
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