posted on 2025-05-11, 11:35authored byDeborah J. Thompson, Tracy A. O'Mara, Lynn Martin, Shirley Hodgson, Kyriaki Michailidou, Jonathan P. Tyrer, Mel J. Maranian, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Peter A. Fasching, Dylan M. Glubb, Katie Ashton, Tony Proietto, Geoffrey Otton, Rodney ScottRodney Scott, Mark McEvoyMark McEvoy, John AttiaJohn Attia, Elizabeth HollidayElizabeth Holliday, Jodie N. Painter, Timothy Cheng, Elizabeth Folkerd, Deborah Doody, Joe Dennis, Penelope M. Webb, Maggie Gorman
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancerandwith 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=4.8x10-11). SNP rs727479 was also among those most strongly associated with circulating E₂ concentrations in 2767 post-menopausal controls (P=7.4x10-8). 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.