Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

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Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

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Figure 1: Plot of the genome-wide association results after fitting the multiplicative model in SNPTEST.
Figure 2: Regional association plots of the associated loci.
Figure 3: Forest plots showing evidence for association at each of the associated loci.

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Acknowledgements

We acknowledge the individuals with Barrett's esophagus who participated in the study and the physicians who helped in recruitment. We thank the many research nurses who also helped recruit, including S. Prew. We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We also thank J. Barrett for design of the Immunochip array. Funding for this study was provided by the WTCCC2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. D.C.W. is supported by a Future Fellowship from the Australian Research Council. S.M. is supported by an Australian National Health & Medical Research Council (NHMRC) Career Development Award. C.C.A.S. was supported by a Wellcome Trust Fellowship (097364/Z/11/Z). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the UK Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls, funded by the Wellcome Trust, and the People of the British Isles collection, funded by the Wellcome Trust. This work was also supported by the Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project (grant C548/A5675) and Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project (grant MGAG1G7R); Cancer Research UK (AspECT, grants C548/A4584 and D9612L00090, and Histological AssessmeNt Determining EpitheliaL Response (HANDEL), grant C548/A9085); AstraZeneca UK educational grant; University Hospitals of Leicester R and D grant; and AspECT (T91 5211 University of Oxford grant HDRMJQ0). The Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) within the BEACON Consortium was supported by US National Institutes of Health grant R01CA13672501. We acknowledge the Dublin Centre for Clinical Research (funded by the Health Research Board and the Wellcome Trust) for support in sample collection and the Irish Blood Transfusion Service and TCD DNA Biobank for provision of control samples. R.M. is supported by the Science Foundation Ireland grant 09/IN.1/B2640.

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J.A.Z.J., I.T., L.J.G. and M.N. oversaw cohort collection for the discovery and replication data sets. N.T., N.B., P.B., S. Paterson, C.E., I.P., K.V., Y.A., I.M., P.P., P. Mullins, H.D., K. Koss, D.C., M. Griffin, D.A., H.W., S. Panter, I.S., H.S., A. Dhar, H.M., H.A., M.R., A.T., D. Morris, C.N., R.L., P.I., C.R., K.R., C.M., C.H., D. Monk, G.D., S.W., D.J., M. Gibbons, S.C., N.C., D.G., S.A., P.W., J.d.C., H.B. and J.A.Z.J. recruited over 50 cases to the AspECT and/or ChOPIN studies. L.J.G., M.N., K.H., P.A., A.M.N. and N.L.G. processed AspECT and/or ChOPIN samples. The AspECT and ChOPIN management groups (P.S., A.T.T., P.B., D.J., M.A., C. Brooks, J.H., D.F., B.R., J.B., S.L., S.A., P.W., S.S., R.F.H., P. Moayyedi, J.d.C., H.B. and J.A.Z.J.) monitored the appropriate use of samples and data from these studies. A.v.d.W., N.T., M.P.P., L.J.W.v.d.L., E.J.K., J.P.H.D., W.H.P., J.V.R., D.P.K., R.M., H.G., H.P., R.B., K. Krishnadath, P.D.S., J.W.P.M.v.B., M.M., R. Petty, R.G. and S.C.C. provided samples as part of the EAGLE Consortium. T.L. was involved in EAGLE project design. The BEACON Consortium (D.C.W., D.L., W.Y., A.H.W., N.C.B., N.J.S., L.J.M., L.B., Y.R., L.J.H., R.Z., D.A.C., H.A.R., B.J.R., M.D.G., G.L., A.G.C., W.-H.C., S.M., W.E. and T.L.V.) provided data on the two lead SNPs for the second replication phase. G.T. and C.W. provided Dutch control samples for the first replication phase. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.D., S.E.H., S.E., E.G., C.L., S.C.P., A.T.-G. and L.P.) executed gnome-wide association study sample handling, genotyping and quality control. The WTCCC2 data and analysis group (Z.S., A.S., C.C.A.S., G.B., C. Bellenguez, C.F., M.P. and P. Donnelly) led the statistical analyses. C.P., E.S., F.L., P.S. and J.-B.C. also undertook statistical analyses. A.S., C.P., I.T., J.A.Z.J., C.C.A.S. and P. Donnelly contributed to writing the manuscript. The WTCCC2 management committee (J.M.B., E.B., M.A.B., J.P.C., A.C., P. Deloukas, P. Donnelly (chairperson), A. Duncanson, J.A.Z.J., H.S.M., C.G.M., C.N.A.P., L.P., R. Plomin, A.R., S.J.S., R.C.T., A.C.V. and N.W.) monitored the execution of the genome-wide association study. All authors reviewed the final manuscript.

Correspondence to Ian Tomlinson or Peter Donnelly or Janusz A Z Jankowski.

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J.A.Z.J. is a consultant to AstraZeneca and is the Chief Investigator of the AspECT and ChOPIN trials.

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A full list of members and affiliations is provided in the Supplementary Note.

A full list of members and affiliations is provided in the Supplementary Note.

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