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

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...

Full description

Bibliographic Details
Main Authors:	Thompson, Deborah J, O'Mara, Tracy A, Glubb, Dylan M, Painter, Jodie N, Cheng, Timothy, Folkerd, Elizabeth, Doody, Deborah, Dennis, Joe, Webb, Penelope M, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley, Michailidou, Kyriaki, Tyrer, Jonathan P, Maranian, Mel J, Hall, Per, Czene, Kamila, Darabi, Hatef, Li, Jingmei, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif B, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Zhao, Hui, Depreeuw, Jeroen, Schrauwen, Stefanie, Amant, Frederic, Goode, Ellen L, Fridley, Brooke L, Dowdy, Sean C, Winham, Stacey J, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica M J, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Carvajal-Carmona, Luis, Tham, Emma, Liu, Tao, Mints, Miriam, Scott, Rodney J, McEvoy, Mark, Attia, John, Holliday, Elizabeth G, Montgomery, Grant W, Martin, Nicholas G, Nyholt, Dale R, Henders, Anjali K, Hopper, John L, Traficante, Nadia, Ruebner, Matthias, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Lambrechts, Diether, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Bolla, Manjeet K, Wang, Qin, Bojesen, Stig E, Shah, Mitul, Luben, Robert, Khaw, Kay-Tee, Pharoah, Paul D P, Dunning, Alison M, Tomlinson, Ian, Dowsett, Mitch, Easton, Douglas F, Spurdle, Amanda B
Format:	Online
Language:	English
Published:	Bioscientifica Ltd 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697192/

id	pubmed-4697192
recordtype	oai_dc
spelling	pubmed-46971922016-02-01 CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer Thompson, Deborah J O'Mara, Tracy A Glubb, Dylan M Painter, Jodie N Cheng, Timothy Folkerd, Elizabeth Doody, Deborah Dennis, Joe Webb, Penelope M Gorman, Maggie Martin, Lynn Hodgson, Shirley Michailidou, Kyriaki Tyrer, Jonathan P Maranian, Mel J Hall, Per Czene, Kamila Darabi, Hatef Li, Jingmei Fasching, Peter A Hein, Alexander Beckmann, Matthias W Ekici, Arif B Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Zhao, Hui Depreeuw, Jeroen Schrauwen, Stefanie Amant, Frederic Goode, Ellen L Fridley, Brooke L Dowdy, Sean C Winham, Stacey J Salvesen, Helga B Trovik, Jone Njolstad, Tormund S Werner, Henrica M J Ashton, Katie Proietto, Tony Otton, Geoffrey Carvajal-Carmona, Luis Tham, Emma Liu, Tao Mints, Miriam Scott, Rodney J McEvoy, Mark Attia, John Holliday, Elizabeth G Montgomery, Grant W Martin, Nicholas G Nyholt, Dale R Henders, Anjali K Hopper, John L Traficante, Nadia Ruebner, Matthias Swerdlow, Anthony J Burwinkel, Barbara Brenner, Hermann Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Lambrechts, Diether Chang-Claude, Jenny Couch, Fergus J Giles, Graham G Kristensen, Vessela N Cox, Angela Bolla, Manjeet K Wang, Qin Bojesen, Stig E Shah, Mitul Luben, Robert Khaw, Kay-Tee Pharoah, Paul D P Dunning, Alison M Tomlinson, Ian Dowsett, Mitch Easton, Douglas F Spurdle, Amanda B Research 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. Bioscientifica Ltd 2016-02 /pmc/articles/PMC4697192/ /pubmed/26574572 http://dx.doi.org/10.1530/ERC-15-0386 Text en © 2016 The authors http://creativecommons.org/licenses/by/3.0/deed.en_GB This work is licensed under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/deed.en_GB)
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Thompson, Deborah J O'Mara, Tracy A Glubb, Dylan M Painter, Jodie N Cheng, Timothy Folkerd, Elizabeth Doody, Deborah Dennis, Joe Webb, Penelope M Gorman, Maggie Martin, Lynn Hodgson, Shirley Michailidou, Kyriaki Tyrer, Jonathan P Maranian, Mel J Hall, Per Czene, Kamila Darabi, Hatef Li, Jingmei Fasching, Peter A Hein, Alexander Beckmann, Matthias W Ekici, Arif B Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Zhao, Hui Depreeuw, Jeroen Schrauwen, Stefanie Amant, Frederic Goode, Ellen L Fridley, Brooke L Dowdy, Sean C Winham, Stacey J Salvesen, Helga B Trovik, Jone Njolstad, Tormund S Werner, Henrica M J Ashton, Katie Proietto, Tony Otton, Geoffrey Carvajal-Carmona, Luis Tham, Emma Liu, Tao Mints, Miriam Scott, Rodney J McEvoy, Mark Attia, John Holliday, Elizabeth G Montgomery, Grant W Martin, Nicholas G Nyholt, Dale R Henders, Anjali K Hopper, John L Traficante, Nadia Ruebner, Matthias Swerdlow, Anthony J Burwinkel, Barbara Brenner, Hermann Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Lambrechts, Diether Chang-Claude, Jenny Couch, Fergus J Giles, Graham G Kristensen, Vessela N Cox, Angela Bolla, Manjeet K Wang, Qin Bojesen, Stig E Shah, Mitul Luben, Robert Khaw, Kay-Tee Pharoah, Paul D P Dunning, Alison M Tomlinson, Ian Dowsett, Mitch Easton, Douglas F Spurdle, Amanda B
spellingShingle	Thompson, Deborah J O'Mara, Tracy A Glubb, Dylan M Painter, Jodie N Cheng, Timothy Folkerd, Elizabeth Doody, Deborah Dennis, Joe Webb, Penelope M Gorman, Maggie Martin, Lynn Hodgson, Shirley Michailidou, Kyriaki Tyrer, Jonathan P Maranian, Mel J Hall, Per Czene, Kamila Darabi, Hatef Li, Jingmei Fasching, Peter A Hein, Alexander Beckmann, Matthias W Ekici, Arif B Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Zhao, Hui Depreeuw, Jeroen Schrauwen, Stefanie Amant, Frederic Goode, Ellen L Fridley, Brooke L Dowdy, Sean C Winham, Stacey J Salvesen, Helga B Trovik, Jone Njolstad, Tormund S Werner, Henrica M J Ashton, Katie Proietto, Tony Otton, Geoffrey Carvajal-Carmona, Luis Tham, Emma Liu, Tao Mints, Miriam Scott, Rodney J McEvoy, Mark Attia, John Holliday, Elizabeth G Montgomery, Grant W Martin, Nicholas G Nyholt, Dale R Henders, Anjali K Hopper, John L Traficante, Nadia Ruebner, Matthias Swerdlow, Anthony J Burwinkel, Barbara Brenner, Hermann Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Lambrechts, Diether Chang-Claude, Jenny Couch, Fergus J Giles, Graham G Kristensen, Vessela N Cox, Angela Bolla, Manjeet K Wang, Qin Bojesen, Stig E Shah, Mitul Luben, Robert Khaw, Kay-Tee Pharoah, Paul D P Dunning, Alison M Tomlinson, Ian Dowsett, Mitch Easton, Douglas F Spurdle, Amanda B CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer
author_facet	Thompson, Deborah J O'Mara, Tracy A Glubb, Dylan M Painter, Jodie N Cheng, Timothy Folkerd, Elizabeth Doody, Deborah Dennis, Joe Webb, Penelope M Gorman, Maggie Martin, Lynn Hodgson, Shirley Michailidou, Kyriaki Tyrer, Jonathan P Maranian, Mel J Hall, Per Czene, Kamila Darabi, Hatef Li, Jingmei Fasching, Peter A Hein, Alexander Beckmann, Matthias W Ekici, Arif B Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Zhao, Hui Depreeuw, Jeroen Schrauwen, Stefanie Amant, Frederic Goode, Ellen L Fridley, Brooke L Dowdy, Sean C Winham, Stacey J Salvesen, Helga B Trovik, Jone Njolstad, Tormund S Werner, Henrica M J Ashton, Katie Proietto, Tony Otton, Geoffrey Carvajal-Carmona, Luis Tham, Emma Liu, Tao Mints, Miriam Scott, Rodney J McEvoy, Mark Attia, John Holliday, Elizabeth G Montgomery, Grant W Martin, Nicholas G Nyholt, Dale R Henders, Anjali K Hopper, John L Traficante, Nadia Ruebner, Matthias Swerdlow, Anthony J Burwinkel, Barbara Brenner, Hermann Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Lambrechts, Diether Chang-Claude, Jenny Couch, Fergus J Giles, Graham G Kristensen, Vessela N Cox, Angela Bolla, Manjeet K Wang, Qin Bojesen, Stig E Shah, Mitul Luben, Robert Khaw, Kay-Tee Pharoah, Paul D P Dunning, Alison M Tomlinson, Ian Dowsett, Mitch Easton, Douglas F Spurdle, Amanda B
author_sort	Thompson, Deborah J
title	CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer
title_short	CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer
title_full	CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer
title_fullStr	CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer
title_full_unstemmed	CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer
title_sort	cyp19a1 fine-mapping and mendelian randomization: estradiol is causal for endometrial cancer
description	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.
publisher	Bioscientifica Ltd
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697192/
_version_	1613518658166849536

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

Similar Items