1. Germline genetic variants and risk of Barrett's esophagus and esophageal adenocarcinoma: a large scale meta-analysis of genome-wide association studies
- Author
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Palles, C, Tomlinson, I, Chegwidden, L, Gharahkhani, P, MacGregor, S, Vaughan, T, Schumacher, J, Jankowski, J, Fitzgerald, R, Gockel, I, Buas, M, May, A, Gerges, C, Anders, M, Becker, J, Kreuser, N, Noder, T, Venerito, M, Veits, L, Schmidt, T, Manner, H, Schmidt, C, Hess, T, Böhmer, A, Izbicki, J, Hölscher, A, Lang, H, Lorenz, D, Schumacher, B, Hackelsberger, A, Mayershofer, R, Pech, O, Vashist, Y, Ott, K, Vieth, M, Weismüller, J, Nöthen, M, Attwood, S, Barr, H, de Caestecker, J, Harrison, R, Love, S, MacDonald, D, Moayyed, P, Prenen, H, Watson, R, Iyer, P, Anderson, L, Bernstein, L, Chow, W, Hardie, L, Lagergren, J, Liu, G, Risch, H, Wu, A, Ye, W, Bird, N, Shaheen, N, Gammon, M, Corley, D, Caldas, C, Moebus, S, Knapp, M, Peters, W, Neuhaus, H, Rösch, T, Ell, C, Pharaoh, P, and Whiteman, D
- Abstract
Background Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA. Methods Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways. Findings We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P Interpretation The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.
- Published
- 2016