Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Shao-Hua Xie; Rui Fang; Mingtao Huang; Juncheng Dai; Aaron Thrift; Lesley Anderson; Wong-Ho Chow; Leslie Bernstein; Marilie D Gammon; Harvey A Risch; Nicholas J Shaheen; Brian J Reid; Anna H Wu; Prasad G Iyer; Geoffrey Liu; Douglas A Corley; David C Whiteman; Carlos Caldas; Paul D. Pharoah; Laura J Hardie; Rebecca C. Fitzgerald; Hongbing Shen; Thomas L Vaughan; Jesper Lagergren

doi:10.1016/j.cgh.2019.11.030

Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Shao-Hua Xie^* (Corresponding Author), Rui Fang, Mingtao Huang, Juncheng Dai, Aaron Thrift, Lesley Anderson, Wong-Ho Chow, Leslie Bernstein, Marilie D Gammon, Harvey A Risch, Nicholas J Shaheen, Brian J Reid, Anna H Wu, Prasad G Iyer, Geoffrey Liu, Douglas A Corley, David C Whiteman, Carlos Caldas, Paul D. Pharoah, Laura J HardieRebecca C. Fitzgerald, Hongbing Shen, Thomas L Vaughan, Jesper Lagergren

^*Corresponding author for this work

Applied Health Sciences

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

11 Citations (Scopus)

Abstract

Background & Aims
Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett’s esophagus (BE).
Methods
We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs.
Results
Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01–1.27) and in women (OR, 1.28; 95% CI, 1.03–1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87–0.99) and in women (OR, 0.93; 95% CI, 0.79–1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77–0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79–1.00) in women. We found no clear associations for other hormones studied, including sex hormone–binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index.
Conclusions
In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

Original language	English
Pages (from-to)	2701-2709.e3
Number of pages	10
Journal	Clinical Gastroenterology and Hepatology
Volume	18
Issue number	12
Early online date	19 Nov 2019
DOIs	https://doi.org/10.1016/j.cgh.2019.11.030
Publication status	Published - Nov 2020

Bibliographical note

Supported by the Bengt Ihres Foundation ( SLS-78016 ), the Ruth and Richard Julin Foundation ( 2018-00137 ), the Swedish Research Council ( 521-2014-2536 and 2015-06275 ), the Swedish Cancer Society ( CAN 2015/460 ), and the National Natural Science Foundation of China ( 8151101160 ).

Keywords

Esophageal Neoplasms
Sex Difference
Gonadal Steroid
Hormones
Causality
QUALITY
MALE PREDOMINANCE
MENDELIAN RANDOMIZATION
STEROID-HORMONES
Gonadal Steroid Hormones
LUTEINIZING-HORMONE
POOLED ANALYSIS
ESOPHAGOGASTRIC JUNCTION
FSH
PROMOTER
GENOME-WIDE ASSOCIATION

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Xie, S.-H., Fang, R., Huang, M., Dai, J., Thrift, A., Anderson, L., Chow, W.-H., Bernstein, L., Gammon, M. D., Risch, H. A., Shaheen, N. J., Reid, B. J., Wu, A. H., Iyer, P. G., Liu, G., Corley, D. A., Whiteman, D. C., Caldas, C., Pharoah, P. D., ... Lagergren, J. (2020). Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus. Clinical Gastroenterology and Hepatology, 18(12), 2701-2709.e3. https://doi.org/10.1016/j.cgh.2019.11.030

Xie, S-H, Fang, R, Huang, M, Dai, J, Thrift, A, Anderson, L, Chow, W-H, Bernstein, L, Gammon, MD, Risch, HA, Shaheen, NJ, Reid, BJ, Wu, AH, Iyer, PG, Liu, G, Corley, DA, Whiteman, DC, Caldas, C, Pharoah, PD, Hardie, LJ, Fitzgerald, RC, Shen, H, Vaughan, TL & Lagergren, J 2020, 'Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus', Clinical Gastroenterology and Hepatology, vol. 18, no. 12, pp. 2701-2709.e3. https://doi.org/10.1016/j.cgh.2019.11.030

@article{1a6e9b6f66b94424a63afe9db79e2e44,

title = "Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett{\textquoteright}s Esophagus",

abstract = "Background & Aims Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett{\textquoteright}s esophagus (BE). Methods We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01–1.27) and in women (OR, 1.28; 95% CI, 1.03–1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87–0.99) and in women (OR, 0.93; 95% CI, 0.79–1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77–0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79–1.00) in women. We found no clear associations for other hormones studied, including sex hormone–binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.",

keywords = "Esophageal Neoplasms, Sex Difference, Gonadal Steroid, Hormones, Causality, QUALITY, MALE PREDOMINANCE, MENDELIAN RANDOMIZATION, STEROID-HORMONES, Gonadal Steroid Hormones, LUTEINIZING-HORMONE, POOLED ANALYSIS, ESOPHAGOGASTRIC JUNCTION, FSH, PROMOTER, GENOME-WIDE ASSOCIATION",

author = "Shao-Hua Xie and Rui Fang and Mingtao Huang and Juncheng Dai and Aaron Thrift and Lesley Anderson and Wong-Ho Chow and Leslie Bernstein and Gammon, {Marilie D} and Risch, {Harvey A} and Shaheen, {Nicholas J} and Reid, {Brian J} and Wu, {Anna H} and Iyer, {Prasad G} and Geoffrey Liu and Corley, {Douglas A} and Whiteman, {David C} and Carlos Caldas and Pharoah, {Paul D.} and Hardie, {Laura J} and Fitzgerald, {Rebecca C.} and Hongbing Shen and Vaughan, {Thomas L} and Jesper Lagergren",

note = "Supported by the Bengt Ihres Foundation ( SLS-78016 ), the Ruth and Richard Julin Foundation ( 2018-00137 ), the Swedish Research Council ( 521-2014-2536 and 2015-06275 ), the Swedish Cancer Society ( CAN 2015/460 ), and the National Natural Science Foundation of China ( 8151101160 ).",

year = "2020",

month = nov,

doi = "10.1016/j.cgh.2019.11.030",

language = "English",

volume = "18",

pages = "2701--2709.e3",

journal = "Clinical Gastroenterology and Hepatology",

issn = "1542-3565",

publisher = "W.B. Saunders Ltd",

number = "12",

}

TY - JOUR

T1 - Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

AU - Xie, Shao-Hua

AU - Fang, Rui

AU - Huang, Mingtao

AU - Dai, Juncheng

AU - Thrift, Aaron

AU - Anderson, Lesley

AU - Chow, Wong-Ho

AU - Bernstein, Leslie

AU - Gammon, Marilie D

AU - Risch, Harvey A

AU - Shaheen, Nicholas J

AU - Reid, Brian J

AU - Wu, Anna H

AU - Iyer, Prasad G

AU - Liu, Geoffrey

AU - Corley, Douglas A

AU - Whiteman, David C

AU - Caldas, Carlos

AU - Pharoah, Paul D.

AU - Hardie, Laura J

AU - Fitzgerald, Rebecca C.

AU - Shen, Hongbing

AU - Vaughan, Thomas L

AU - Lagergren, Jesper

N1 - Supported by the Bengt Ihres Foundation ( SLS-78016 ), the Ruth and Richard Julin Foundation ( 2018-00137 ), the Swedish Research Council ( 521-2014-2536 and 2015-06275 ), the Swedish Cancer Society ( CAN 2015/460 ), and the National Natural Science Foundation of China ( 8151101160 ).

PY - 2020/11

Y1 - 2020/11

N2 - Background & Aims Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett’s esophagus (BE). Methods We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01–1.27) and in women (OR, 1.28; 95% CI, 1.03–1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87–0.99) and in women (OR, 0.93; 95% CI, 0.79–1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77–0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79–1.00) in women. We found no clear associations for other hormones studied, including sex hormone–binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

AB - Background & Aims Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett’s esophagus (BE). Methods We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01–1.27) and in women (OR, 1.28; 95% CI, 1.03–1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87–0.99) and in women (OR, 0.93; 95% CI, 0.79–1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77–0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79–1.00) in women. We found no clear associations for other hormones studied, including sex hormone–binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

KW - Esophageal Neoplasms

KW - Sex Difference

KW - Gonadal Steroid

KW - Hormones

KW - Causality

KW - QUALITY

KW - MALE PREDOMINANCE

KW - MENDELIAN RANDOMIZATION

KW - STEROID-HORMONES

KW - Gonadal Steroid Hormones

KW - LUTEINIZING-HORMONE

KW - POOLED ANALYSIS

KW - ESOPHAGOGASTRIC JUNCTION

KW - FSH

KW - PROMOTER

KW - GENOME-WIDE ASSOCIATION

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U2 - 10.1016/j.cgh.2019.11.030

DO - 10.1016/j.cgh.2019.11.030

M3 - Article

SN - 1542-3565

VL - 18

SP - 2701-2709.e3

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

IS - 12

ER -

Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Abstract

Bibliographical note

Keywords

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