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 Bernstein; Douglas 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

doi:10.1093/carcin/bgaa132

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^* (Corresponding Author), Matthew F Buas^* (Corresponding Author)

^*Corresponding author for this work

Applied Health Sciences

Research output: Contribution to journal › Article › peer-review

10 Citations (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 language	English
Pages (from-to)	369-377
Number of pages	9
Journal	Carcinogenesis
Volume	42
Issue number	3
Early online date	10 Dec 2020
DOIs	https://doi.org/10.1093/carcin/bgaa132
Publication status	Published - Mar 2021

Bibliographical note

Funding
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/carcin/bgaa132Licence: Unspecified

Cite this

Dighe, S. G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D. M., Palles, C., Ye, W., Gammon, M. D., Iyer, P. G., Anderson, L. A., Liu, G., Wu, A. H., Dai, J. Y., Chow, W.-H., Risch, H. A., Lagergren, J., Shaheen, N. J., ... Buas, M. F. (2021). Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis, 42(3), 369-377. https://doi.org/10.1093/carcin/bgaa132

Dighe, SG, Chen, J, Yan, L, He, Q, Gharahkhani, P, Onstad, L, Levine, DM, Palles, C, Ye, W, Gammon, MD, Iyer, PG, Anderson, LA, Liu, G, Wu, AH, Dai, JY, Chow, W-H, Risch, HA, Lagergren, J, Shaheen, NJ, Bernstein, L, Corley, DA, Prenen, H, deCaestecker, J, MacDonald, D, Moayyedi, P, Barr, H, Love, SB, Chegwidden, L, Attwood, S, Watson, P, Harrison, R, Ott, K, Moebus, S, Venerito, M, Lang, H, Mayershofer, R, Knapp, M, Veits, L, Gerges, C, Weismüller, J, Gockel, I, Vashist, Y, Nöthen, MM, Izbicki, JR, Manner, H, Neuhaus, H, Rösch, T, Böhmer, AC, Hölscher, AH, Anders, M, Pech, O, Schumacher, B, Schmidt, C, Schmidt, T, Noder, T, Lorenz, D, Vieth, M, May, A, Hess, T, Kreuser, N, Becker, J, Ell, C, Ambrosone, CB, Moysich, KB, MacGregor, S, Tomlinson, I, Whiteman, DC, Jankowski, J, Schumacher, J, Vaughan, TL, Madeleine, MM, Hardie, LJ & Buas, MF 2021, 'Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma', Carcinogenesis, vol. 42, no. 3, pp. 369-377. https://doi.org/10.1093/carcin/bgaa132

@article{46f7325e04e14dd7a719fb8fbaee824d,

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

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.",

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

note = "Funding 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 Kr{\"o}ner 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",

year = "2021",

month = mar,

doi = "10.1093/carcin/bgaa132",

language = "English",

volume = "42",

pages = "369--377",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

AU - Dighe, Shruti G

AU - Chen, Jianhong

AU - Yan, Li

AU - He, Qianchuan

AU - Gharahkhani, Puya

AU - Onstad, Lynn

AU - Levine, David M

AU - Palles, Claire

AU - Ye, Weimin

AU - Gammon, Marilie D

AU - Iyer, Prasad G

AU - Anderson, Lesley A

AU - Liu, Geoffrey

AU - Wu, Anna H

AU - Dai, James Y

AU - Chow, Wong-Ho

AU - Risch, Harvey A

AU - Lagergren, Jesper

AU - Shaheen, Nicholas J

AU - Bernstein, Leslie

AU - Corley, Douglas A

AU - Prenen, Hans

AU - deCaestecker, John

AU - MacDonald, David

AU - Moayyedi, Paul

AU - Barr, Hugh

AU - Love, Sharon B

AU - Chegwidden, Laura

AU - Attwood, Stephen

AU - Watson, Peter

AU - Harrison, Rebecca

AU - Ott, Katja

AU - Moebus, Susanne

AU - Venerito, Marino

AU - Lang, Hauke

AU - Mayershofer, Rupert

AU - Knapp, Michael

AU - Veits, Lothar

AU - Gerges, Christian

AU - Weismüller, Josef

AU - Gockel, Ines

AU - Vashist, Yogesh

AU - Nöthen, Markus M

AU - Izbicki, Jakob R

AU - Manner, Hendrik

AU - Neuhaus, Horst

AU - Rösch, Thomas

AU - Böhmer, Anne C

AU - Hölscher, Arnulf H

AU - Anders, Mario

AU - Pech, Oliver

AU - Schumacher, Brigitte

AU - Schmidt, Claudia

AU - Schmidt, Thomas

AU - Noder, Tania

AU - Lorenz, Dietmar

AU - Vieth, Michael

AU - May, Andrea

AU - Hess, Timo

AU - Kreuser, Nicole

AU - Becker, Jessica

AU - Ell, Christian

AU - Ambrosone, Christine B

AU - Moysich, Kirsten B

AU - MacGregor, Stuart

AU - Tomlinson, Ian

AU - Whiteman, David C

AU - Jankowski, Janusz

AU - Schumacher, Johannes

AU - Vaughan, Thomas L

AU - Madeleine, Margaret M

AU - Hardie, Laura J

AU - Buas, Matthew F

N1 - Funding 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

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

U2 - 10.1093/carcin/bgaa132

DO - 10.1093/carcin/bgaa132

M3 - Article

C2 - 33300568

SN - 0143-3334

VL - 42

SP - 369

EP - 377

JO - Carcinogenesis

JF - Carcinogenesis

IS - 3

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Fingerprint

Cite this