CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Deborah J Thompson; Tracy A O'Mara; Dylan M Glubb; Jodie N Painter; Timothy Cheng; Elizabeth Folkerd; Deborah Doody; Joe Dennis; Penelope M Webb; Maggie Gorman; Lynn Martin; Shirley Hodgson; Kyriaki Michailidou; Jonathan P Tyrer; Mel J Maranian; Per Hall; Kamila Czene; Hatef Darabi; Jingmei Li; Peter A Fasching; Alexander Hein; Matthias W Beckmann; Arif B Ekici; Thilo Dörk; Peter Hillemanns; Matthias Dürst; Ingo Runnebaum; Hui Zhao; Jeroen Depreeuw; Stefanie Schrauwen; Frederic Amant; Ellen L Goode; Brooke L Fridley; Sean C Dowdy; Stacey J Winham; Helga B Salvesen; Jone Trovik; Tormund S Njolstad; Henrica M J Werner; Katie Ashton; Tony Proietto; Geoffrey Otton; Luis Carvajal-Carmona; Emma Tham; Tao Liu; Miriam Mints; Rodney J Scott; Mark McEvoy; John Attia; Stig E Bojesen; Australian National Endometrial Cancer Study Group (ANECS)

doi:10.1530/ERC-15-0386

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Deborah J Thompson, Tracy A O'Mara, Dylan M Glubb, Jodie N Painter, Timothy Cheng, Elizabeth Folkerd, Deborah Doody, Joe Dennis, Penelope M Webb, Maggie Gorman, Lynn Martin, Shirley Hodgson, Kyriaki Michailidou, Jonathan P Tyrer, Mel J Maranian, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Peter A FaschingAlexander Hein, Matthias W Beckmann, Arif B Ekici, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Hui Zhao, Jeroen Depreeuw, Stefanie Schrauwen, Frederic Amant, Ellen L Goode, Brooke L Fridley, Sean C Dowdy, Stacey J Winham, Helga B Salvesen, Jone Trovik, Tormund S Njolstad, Henrica M J Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Luis Carvajal-Carmona, Emma Tham, Tao Liu, Miriam Mints, Rodney J Scott, Mark McEvoy, John Attia, Stig E Bojesen, Australian National Endometrial Cancer Study Group (ANECS)

Department of Clinical Biochemistry

58 Citations (Scopus)

Abstract

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Original language	English
Journal	Endocrine-Related Cancer
Volume	23
Issue number	2
Pages (from-to)	77-91
Number of pages	15
ISSN	1351-0088
DOIs	https://doi.org/10.1530/ERC-15-0386
Publication status	Published - Feb 2016

Keywords

Age Factors
Alleles
Aromatase
Body Mass Index
Case-Control Studies
Endometrial Neoplasms
Estradiol
Female
Gene-Environment Interaction
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Humans
Phenotype
Polymorphism, Single Nucleotide
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

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10.1530/ERC-15-0386

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Thompson, D. J., O'Mara, T. A., Glubb, D. M., Painter, J. N., Cheng, T., Folkerd, E., Doody, D., Dennis, J., Webb, P. M., Gorman, M., Martin, L., Hodgson, S., Michailidou, K., Tyrer, J. P., Maranian, M. J., Hall, P., Czene, K., Darabi, H., Li, J., ... Australian National Endometrial Cancer Study Group (ANECS) (2016). CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Endocrine-Related Cancer, 23(2), 77-91. https://doi.org/10.1530/ERC-15-0386

Thompson, DJ, O'Mara, TA, Glubb, DM, Painter, JN, Cheng, T, Folkerd, E, Doody, D, Dennis, J, Webb, PM, Gorman, M, Martin, L, Hodgson, S, Michailidou, K, Tyrer, JP, Maranian, MJ, Hall, P, Czene, K, Darabi, H, Li, J, Fasching, PA, Hein, A, Beckmann, MW, Ekici, AB, Dörk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Zhao, H, Depreeuw, J, Schrauwen, S, Amant, F, Goode, EL, Fridley, BL, Dowdy, SC, Winham, SJ, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Carvajal-Carmona, L, Tham, E, Liu, T, Mints, M, Scott, RJ, McEvoy, M, Attia, J, Bojesen, SE & Australian National Endometrial Cancer Study Group (ANECS) 2016, 'CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer', Endocrine-Related Cancer, vol. 23, no. 2, pp. 77-91. https://doi.org/10.1530/ERC-15-0386

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title = "CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer",

abstract = "Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.",

keywords = "Age Factors, Alleles, Aromatase, Body Mass Index, Case-Control Studies, Endometrial Neoplasms, Estradiol, Female, Gene-Environment Interaction, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",

author = "Thompson, \{Deborah J\} and O'Mara, \{Tracy A\} and Glubb, \{Dylan M\} and Painter, \{Jodie N\} and Timothy Cheng and Elizabeth Folkerd and Deborah Doody and Joe Dennis and Webb, \{Penelope M\} and Maggie Gorman and Lynn Martin and Shirley Hodgson and Kyriaki Michailidou and Tyrer, \{Jonathan P\} and Maranian, \{Mel J\} and Per Hall and Kamila Czene and Hatef Darabi and Jingmei Li and Fasching, \{Peter A\} and Alexander Hein and Beckmann, \{Matthias W\} and Ekici, \{Arif B\} and Thilo D{\"o}rk and Peter Hillemanns and Matthias D{\"u}rst and Ingo Runnebaum and Hui Zhao and Jeroen Depreeuw and Stefanie Schrauwen and Frederic Amant and Goode, \{Ellen L\} and Fridley, \{Brooke L\} and Dowdy, \{Sean C\} and Winham, \{Stacey J\} and Salvesen, \{Helga B\} and Jone Trovik and Njolstad, \{Tormund S\} and Werner, \{Henrica M J\} and Katie Ashton and Tony Proietto and Geoffrey Otton and Luis Carvajal-Carmona and Emma Tham and Tao Liu and Miriam Mints and Scott, \{Rodney J\} and Mark McEvoy and John Attia and Bojesen, \{Stig E\} and \{Australian National Endometrial Cancer Study Group (ANECS)\}",

note = "{\textcopyright} 2016 The authors.",

year = "2016",

month = feb,

doi = "10.1530/ERC-15-0386",

language = "English",

volume = "23",

pages = "77--91",

journal = "Endocrine-Related Cancer",

issn = "1351-0088",

publisher = "BioScientifica Ltd.",

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TY - JOUR

T1 - CYP19A1 fine-mapping and Mendelian randomization

T2 - estradiol is causal for endometrial cancer

AU - Thompson, Deborah J

AU - O'Mara, Tracy A

AU - Glubb, Dylan M

AU - Painter, Jodie N

AU - Cheng, Timothy

AU - Folkerd, Elizabeth

AU - Doody, Deborah

AU - Dennis, Joe

AU - Webb, Penelope M

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Hodgson, Shirley

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P

AU - Maranian, Mel J

AU - Hall, Per

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Fasching, Peter A

AU - Hein, Alexander

AU - Beckmann, Matthias W

AU - Ekici, Arif B

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Runnebaum, Ingo

AU - Zhao, Hui

AU - Depreeuw, Jeroen

AU - Schrauwen, Stefanie

AU - Amant, Frederic

AU - Goode, Ellen L

AU - Fridley, Brooke L

AU - Dowdy, Sean C

AU - Winham, Stacey J

AU - Salvesen, Helga B

AU - Trovik, Jone

AU - Njolstad, Tormund S

AU - Werner, Henrica M J

AU - Ashton, Katie

AU - Proietto, Tony

AU - Otton, Geoffrey

AU - Carvajal-Carmona, Luis

AU - Tham, Emma

AU - Liu, Tao

AU - Mints, Miriam

AU - Scott, Rodney J

AU - McEvoy, Mark

AU - Attia, John

AU - Bojesen, Stig E

AU - Australian National Endometrial Cancer Study Group (ANECS)

PY - 2016/2

Y1 - 2016/2

N2 - Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

AB - Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

KW - Age Factors

KW - Alleles

KW - Aromatase

KW - Body Mass Index

KW - Case-Control Studies

KW - Endometrial Neoplasms

KW - Estradiol

KW - Female

KW - Gene-Environment Interaction

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

UR - https://www.scopus.com/pages/publications/84956730658

U2 - 10.1530/ERC-15-0386

DO - 10.1530/ERC-15-0386

M3 - Journal article

C2 - 26574572

SN - 1351-0088

VL - 23

SP - 77

EP - 91

JO - Endocrine-Related Cancer

JF - Endocrine-Related Cancer

IS - 2

ER -

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

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Keywords

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