CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Thompson, D. J., O'Mara, T. A., Glubb, D. M., Painter, J. N., Cheng, T., Folkerd, E., Doody, D., Dennis, J., Webb, P. M., Australian National Endometrial Cancer Study Group (ANECS), Gorman, M., Martin, L., Hodgson, S., National Study of Endometrial Cancer Genetics Group (NSECG), Michailidou, K., Tyrer, J. P., Maranian, M. J., Hall, P., Czene, K., Darabi, H., Li, J., Fasching, P. A., Hein, A., Beckmann, M. W., Ekici, A. B., Dörk, T., Hillemanns, P., Dürst, M., Runnebaum, I., Zhao, H., Depreeuw, J., Schrauwen, S., Amant, F., Goode, E. L., Fridley, B. L., Dowdy, S. C., Winham, S. J., Salvesen, H. B., Trovik, J., Njolstad, T. S., Werner, H. M. J., Ashton, K., Proietto, T., Otton, G., Carvajal-Carmona, L., Tham, E., Liu, T., Mints, M., for RENDOCAS, Scott, R. J., McEvoy, M., Attia, J., Holliday, E. G., Montgomery, G. W., Martin, N. G., Nyholt, D. R., Henders, A. K., Hopper, J. L., Traficante, N., AOCS Group, Ruebner, M., Swerdlow, A. J., Burwinkel, B., Brenner, H., Meindl, A., Brauch, H., Lindblom, A., Lambrechts, D., Chang-Claude, J., Couch, F. J., Giles, G. G., Kristensen, V. N., Cox, A., Bolla, M. K., Wang, Q., Bojesen, S. E., Shah, M., Luben, R., Khaw, K., Pharoah, P. D. P., Dunning, A. M., Tomlinson, I., Dowsett, M., Easton, D. F., & Spurdle, A. B. Endocrine-Related Cancer, 23(2):77–91, February, 2016.
doi  abstract   bibtex   
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.
@article{thompson_cyp19a1_2016,
	title = {{CYP19A1} fine-mapping and {Mendelian} randomization: estradiol is causal for endometrial cancer},
	volume = {23},
	issn = {1479-6821},
	shorttitle = {{CYP19A1} fine-mapping and {Mendelian} randomization},
	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.},
	language = {eng},
	number = {2},
	journal = {Endocrine-Related Cancer},
	author = {Thompson, Deborah J. and O'Mara, Tracy A. and Glubb, Dylan M. and Painter, Jodie N. and Cheng, Timothy and Folkerd, Elizabeth and Doody, Deborah and Dennis, Joe and Webb, Penelope M. and {Australian National Endometrial Cancer Study Group (ANECS)} and Gorman, Maggie and Martin, Lynn and Hodgson, Shirley and {National Study of Endometrial Cancer Genetics Group (NSECG)} and Michailidou, Kyriaki and Tyrer, Jonathan P. and Maranian, Mel J. and Hall, Per and Czene, Kamila and Darabi, Hatef and Li, Jingmei and Fasching, Peter A. and Hein, Alexander and Beckmann, Matthias W. and Ekici, Arif B. and Dörk, Thilo and Hillemanns, Peter and Dürst, Matthias and Runnebaum, Ingo and Zhao, Hui and Depreeuw, Jeroen and Schrauwen, Stefanie and Amant, Frederic and Goode, Ellen L. and Fridley, Brooke L. and Dowdy, Sean C. and Winham, Stacey J. and Salvesen, Helga B. and Trovik, Jone and Njolstad, Tormund S. and Werner, Henrica M. J. and Ashton, Katie and Proietto, Tony and Otton, Geoffrey and Carvajal-Carmona, Luis and Tham, Emma and Liu, Tao and Mints, Miriam and {for RENDOCAS} and Scott, Rodney J. and McEvoy, Mark and Attia, John and Holliday, Elizabeth G. and Montgomery, Grant W. and Martin, Nicholas G. and Nyholt, Dale R. and Henders, Anjali K. and Hopper, John L. and Traficante, Nadia and {AOCS Group} and Ruebner, Matthias and Swerdlow, Anthony J. and Burwinkel, Barbara and Brenner, Hermann and Meindl, Alfons and Brauch, Hiltrud and Lindblom, Annika and Lambrechts, Diether and Chang-Claude, Jenny and Couch, Fergus J. and Giles, Graham G. and Kristensen, Vessela N. and Cox, Angela and Bolla, Manjeet K. and Wang, Qin and Bojesen, Stig E. and Shah, Mitul and Luben, Robert and Khaw, Kay-Tee and Pharoah, Paul D. P. and Dunning, Alison M. and Tomlinson, Ian and Dowsett, Mitch and Easton, Douglas F. and Spurdle, Amanda B.},
	month = feb,
	year = {2016},
	pmid = {26574572},
	pmcid = {PMC4697192},
	keywords = {Age Factors, Alleles, Aromatase, Body Mass Index, CYP19A1, Case-Control Studies, Endometrial Neoplasms, Estradiol, Female, Gene-Environment Interaction, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, endometrial cancer, estradiol},
	pages = {77--91},
}

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