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.
This work was principally supported by the National Institutes of Health (R21DK099804 to M.M.M.; R01CA136725 to T.L.V. and D.C.W.; P30CA016056 to the Roswell Park Comprehensive Cancer Center). Support for studies related to the Bonn dataset was granted by the Else Kröner Fresenius Stiftung (EKFS) (grant number 2013_A118 awarded to I.G. and J.S.). M.M.N. received support from the Alfried Krupp von Bohlen und Halbach-Stiftung and is a member of the DFG funded Excellence Cluster ImmunoSensation. The Heinz Nixdorf Recall cohort was established with the generous support of the Heinz Nixdorf Foundation, Germany. Additional funding sources for individual studies included in the BEACON GWAS, and for BEACON investigators, have been acknowledged previously. Study sponsors played no role in the study design, collection, analysis or interpretation of the data, or in the writing of the report