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

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 M, Ekici AB, Doerk T, Hillemanns P, Duerst 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, Holliday EG, Montgomery GW, Martin NG, Nyholt DR, Henders AK, Hopper JL, Traficante N, Rübner M, Swerdlow AJ, Burwinkel B, Brenner H, Meindl A, Brauch H, Lindblom A, Lambrechts D, Chang-Claude J, Couch FJ, Giles GG, Kristensen VN, Cox A, Bolla MK, Wang Q, Bojesen SE, Shah M, Luben R, Khaw KT, Pharoah PDP, Dunning AM, Tomlinson I, Dowsett M, Easton DF, Spurdle AB (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 23

Pages Range: 77-91

Journal Issue: 2

DOI: 10.1530/ERC-15-0386

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.

Authors with CRIS profile

Involved external institutions

Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Karolinska Institute Sweden (SE) University of Copenhagen Denmark (DK) University of Cambridge United Kingdom (GB) University of Oxford United Kingdom (GB) Royal Marsden Hospital / The Royal Marsden NHS Foundation Trust United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB) University of California Los Angeles (UCLA) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Friedrich-Schiller-Universität Jena Germany (DE) Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC)) Belgium (BE) Mayo Clinic United States (USA) (US) University of Kansas (KU) United States (USA) (US) University of Bergen / Universitetet i Bergen Norway (NO) John Hunter Hospital Australia (AU) University of Newcastle (UoN) Australia (AU) Universidad del Tolima Colombia (CO) The University of Melbourne Australia (AU) The Institute of Cancer Research (ICR) United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Technische Universität München (TUM) Germany (DE) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) University of Sheffield United Kingdom (GB)

How to cite

APA:

Thompson, D.J., O'Mara, T.A., Glubb, D.M., Painter, J.N., Cheng, T., Folkerd, E.,... Spurdle, A.B. (2016). CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Endocrine-Related Cancer, 23(2), 77-91. https://dx.doi.org/10.1530/ERC-15-0386

MLA:

Thompson, Deborah J., et al. "CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer." Endocrine-Related Cancer 23.2 (2016): 77-91.

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