Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Shruti G Dighe, Jianhong Chen, Li Yan, Qianchuan He, Puya Gharahkhani, Lynn Onstad, David M Levine, Claire Palles, Weimin Ye, Marilie D Gammon, Prasad G Iyer, Lesley A Anderson, Geoffrey Liu, Anna H Wu, James Y Dai, Wong-Ho Chow, Harvey A Risch, Jesper Lagergren, Nicholas J Shaheen, Leslie BernsteinDouglas A Corley, Hans Prenen, John deCaestecker, David MacDonald, Paul Moayyedi, Hugh Barr, Sharon B Love, Laura Chegwidden, Stephen Attwood, Peter Watson, Rebecca Harrison, Katja Ott, Susanne Moebus, Marino Venerito, Hauke Lang, Rupert Mayershofer, Michael Knapp, Lothar Veits, Christian Gerges, Josef Weismüller, Ines Gockel, Yogesh Vashist, Markus M Nöthen, Jakob R Izbicki, Hendrik Manner, Horst Neuhaus, Thomas Rösch, Anne C Böhmer, Arnulf H Hölscher, Mario Anders, Oliver Pech, Brigitte Schumacher, Claudia Schmidt, Thomas Schmidt, Tania Noder, Dietmar Lorenz, Michael Vieth, Andrea May, Timo Hess, Nicole Kreuser, Jessica Becker, Christian Ell, Christine B Ambrosone, Kirsten B Moysich, Stuart MacGregor, Ian Tomlinson, David C Whiteman, Janusz Jankowski, Johannes Schumacher, Thomas L Vaughan, Margaret M Madeleine, Laura J Hardie, Matthew F Buas

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling, and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal components analysis (PCA) was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 SNPs in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases, and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17,159 controls). Global variation in the IGF pathway was associated with risk of BE (P=0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; p=0.00046, FDR q=0.0056) and IGF1R (IGF1 receptor; p=0.0090, q=0.0542). These gene-level signals remained significant at q<0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Original languageEnglish
Pages (from-to)369-377
Number of pages9
JournalCarcinogenesis
Volume42
Issue number3
Early online date10 Dec 2020
DOIs
Publication statusPublished - Mar 2021

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