Matthew F Buas1, Qianchuan He1, Lisa G Johnson1, Lynn Onstad1, David M Levine2, Aaron P Thrift3, Puya Gharahkhani4, Claire Palles5, Jesper Lagergren6,7, Rebecca C Fitzgerald8, Weimin Ye9, Carlos Caldas10, Nigel C Bird11, Nicholas J Shaheen12, Leslie Bernstein13, Marilie D Gammon14, Anna H Wu15, Laura J Hardie16, Paul D Pharoah17,18, Geoffrey Liu19, Prassad Iyer20, Douglas A Corley21,22, Harvey A Risch23, Wong-Ho Chow24, Hans Prenen25, Laura Chegwidden26, Sharon Love27, Stephen Attwood28, Paul Moayyedi29, David MacDonald30, Rebecca Harrison31, Peter Watson32, Hugh Barr33, John deCaestecker34, Ian Tomlinson5, Janusz Jankowski35, David C Whiteman36, Stuart MacGregor4, Thomas L Vaughan1,37, Margaret M Madeleine1,37. 1. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2. Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington, USA. 3. Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA. 4. Queensland Institute of Medical Research Berghofer Medical Research Institute Brisbane, Queensland, Australia. 5. Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK. 6. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 7. Division of Cancer Studies, King's College London, UK. 8. Medical Research Council (MRC) MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK. 9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 10. Cancer Research UK, Cambridge Institute, Cambridge, UK. 11. Department of Oncology, Medical School, University of Sheffield, Sheffield, UK. 12. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. 13. Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA. 14. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. 15. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA. 16. Division of Epidemiology, University of Leeds, Leeds, UK. 17. Department of Oncology, University of Cambridge, Cambridge, UK. 18. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 19. Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada. 20. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. 21. Division of Research, Kaiser Permanente Northern California, Oakland, California, USA. 22. San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA. 23. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. 24. Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA. 25. Department of Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium. 26. University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. 27. Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK. 28. Department of General Surgery, North Tyneside General Hospital, North Shields, UK. 29. Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 30. Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 31. Department of Pathology, Leicester Royal Infirmary, Leicester, UK. 32. Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK. 33. Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK. 34. Department of Gastroenterology, Leicester General Hospital, Leicester, UK. 35. UClan Medical School, West Lakes Campus, Rm 127 Lindow Centre, Cumbria, UK. 36. Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 37. Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, USA.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Entities:
Keywords:
BARRETT'S OESOPHAGUS; GENETIC POLYMORPHISMS; INFLAMMATION; OESOPHAGEAL CANCER
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