Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Jing Dong; Carlo Maj; Spiridon Tsavachidis; Quinn T Ostrom; Puya Gharahkhani; Lesley A Anderson; Anna H Wu; Weimin Ye; Leslie Bernstein; Oleg Borisov; Julia Schröder; Wong-Ho Chow; Marilie D Gammon; Geoffrey Liu; Carlos Caldas; Paul D Pharoah; Harvey A Risch; Andrea May; Christian Gerges; Mario Anders; Marino Venerito; Thomas Schmidt; Jakob R Izbicki; Arnulf H Hölscher; Brigitte Schumacher; Yogesh Vashist; Horst Neuhaus; Thomas Rösch; Michael Knapp; Peter Krawitz; Anne Böhmer; Prasad G Iyer; Brian J Reid; Jesper Lagergren; Nicholas J Shaheen; Douglas A Corley; Ines Gockel; Rebecca C Fitzgerald; Stomach and Oesophageal Cancer Study (SOCS) consortium; Michael B Cook; David C Whiteman; Thomas L Vaughan; Johannes Schumacher; Aaron P Thrift

doi:10.1053/j.gastro.2020.08.052

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Gastroenterology. 2020 Dec;159(6):2065-2076.e1. doi: 10.1053/j.gastro.2020.08.052. Epub 2020 Sep 9.

Authors

Jing Dong¹, Carlo Maj², Spiridon Tsavachidis³, Quinn T Ostrom³, Puya Gharahkhani⁴, Lesley A Anderson⁵, Anna H Wu⁶, Weimin Ye⁷, Leslie Bernstein⁸, Oleg Borisov², Julia Schröder⁹, Wong-Ho Chow¹⁰, Marilie D Gammon¹¹, Geoffrey Liu¹², Carlos Caldas¹³, Paul D Pharoah¹⁴, Harvey A Risch¹⁵, Andrea May¹⁶, Christian Gerges¹⁷, Mario Anders¹⁸, Marino Venerito¹⁹, Thomas Schmidt²⁰, Jakob R Izbicki²¹, Arnulf H Hölscher²², Brigitte Schumacher²³, Yogesh Vashist²¹, Horst Neuhaus¹⁷, Thomas Rösch²⁴, Michael Knapp²⁵, Peter Krawitz², Anne Böhmer⁹, Prasad G Iyer²⁶, Brian J Reid²⁷, Jesper Lagergren²⁸, Nicholas J Shaheen²⁹, Douglas A Corley³⁰, Ines Gockel³¹, Rebecca C Fitzgerald³²; Stomach and Oesophageal Cancer Study (SOCS) consortium; Michael B Cook³³, David C Whiteman³⁴, Thomas L Vaughan²⁷, Johannes Schumacher³⁵, Aaron P Thrift³⁶

Collaborators

Stomach and Oesophageal Cancer Study (SOCS) consortium:
Jing Dong, Carlo Maj, Spiridon Tsavachidis, Quinn T Ostrom, Puya Gharahkhani, Lesley A Anderson, Anna H Wu, Weimin Ye, Leslie Bernstein, Oleg Borisov, Julia Schröder, Wong-Ho Chow, Marilie D Gammon, Geoffrey Liu, Carlos Caldas, Paul D Pharoah, Harvey A Risch, Andrea May, Christian Gerges, Mario Anders, Marino Venerito, Thomas Schmidt, Jakob R Izbicki, Arnulf H Hölscher, Brigitte Schumacher, Yogesh Vashist, Horst Neuhaus, Thomas Rösch, Michael Knapp, Peter Krawitz, Anne Böhmer, Prasad G Iyer, Brian J Reid, Jesper Lagergren, Nicholas J Shaheen, Douglas A Corley, Ines Gockel, Rebecca C Fitzgerald, Michael B Cook, David C Whiteman, Thomas L Vaughan, Johannes Schumacher, Aaron P Thrift

Affiliations

¹ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
² Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany.
³ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
⁴ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵ Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland & Aberdeen Center for Health Data Science, University of Aberdeen, Scotland.
⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.
⁹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁰ Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.
¹¹ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
¹² Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada.
¹³ Cancer Research UK, Cambridge Institute, Cambridge, UK.
¹⁴ Department of Oncology, University of Cambridge, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁵ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
¹⁶ Department of Medicine II, Sana Klinikum, Offenbach, Germany.
¹⁷ Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany.
¹⁸ Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany.
¹⁹ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.
²⁰ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
²¹ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany.
²² Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
²³ Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany.
²⁴ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
²⁵ Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
²⁶ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
²⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
²⁸ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
²⁹ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
³⁰ Division of Research, Kaiser Permanente Northern California, Oakland, California; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.
³¹ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
³² Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
³³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
³⁴ Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³⁵ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
³⁶ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: aaron.thrift@bcm.edu.

Abstract

Background & aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P_BONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P_BONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals.

Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Keywords: Barrett’s esophagus; Genome-Wide Association Study; Interaction; Sex Difference.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / epidemiology
Adenocarcinoma / genetics*
Barrett Esophagus / epidemiology
Barrett Esophagus / genetics*
Biomarkers, Tumor / genetics*
Case-Control Studies
Esophageal Neoplasms / epidemiology
Esophageal Neoplasms / genetics*
Eye Proteins / genetics
Female
Gastroesophageal Reflux / epidemiology
Gastroesophageal Reflux / genetics
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Male
Obesity / epidemiology
Obesity / genetics
Polymorphism, Single Nucleotide
RNA-Binding Proteins / genetics
Risk Assessment
Risk Factors
Serine Endopeptidases / genetics
Sex Factors

Substances

Biomarkers, Tumor
Eye Proteins
KHDRBS2 protein, human
Prss55 protein, human
RNA-Binding Proteins
RP1L1 protein, human
Serine Endopeptidases

Supplementary concepts

Adenocarcinoma Of Esophagus

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding