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., Australian National Endometrial Cancer Study Group (ANECS) None., Gorman M., Martin L., Hodgson S., National Study of Endometrial Cancer Genetics Group (NSECG) None., 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., for RENDOCAS None., Scott RJ., McEvoy M., Attia J., Holliday EG., Montgomery GW., Martin NG., Nyholt DR., Henders AK., Hopper JL., Traficante N., AOCS Group None., Ruebner 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 K-T., Pharoah PDP., Dunning AM., Tomlinson I., Dowsett M., Easton DF., Spurdle 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.