CYP19A1 fine-mapping and Mendelian randomization

Research output: Contribution to journalJournal articleResearchpeer-review

Deborah J Thompson, Tracy A O'Mara, Dylan M Glubb, Jodie N Painter, Timothy Cheng, Elizabeth J 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 & 61 others Alexander Hein, Matthias W Beckmann, Arif B Ekici, Thilo Doerk, Peter Hillemanns, Matthias Durst, 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 G McEvoy, John R Attia, Elizabeth G Holliday, Grant W. Montgomery, Nicholas G. Martin, Dale R Nyholt, Anjali K Henders, John L Hopper, Nadia Traficante, Matthias Ruebner, Anthony J Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Diether Lambrechts, Jenny Chang-Claude, Fergus J Couch, Graham Giles, Vessela N Kristensen, Angela Cox, Manjeet K Bolla, Qin Wang, Stig E Bojesen, Mitul Shah, Robert Luben, Kay-Tee Khaw, Paul P D Pharoah, Alison M Dunning, Ian Tomlinson, Mitch Dowsett, Douglas F Easton, Amanda B Spurdle

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 languageEnglish
JournalEndocrine - Related Cancer
Volume23
Pages (from-to)77-91
Number of pages15
ISSN1351-0088
DOIs
Publication statusPublished - 1 Feb 2016

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