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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)Gorman M, Martin L, Hodgson S, National Study of Endometrial Cancer Genetics Group (NSECG)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 HM, Ashton K, Proietto T, Otton G, Carvajal-Carmona L, Tham E, Liu T, Mints M, for RENDOCASScott RJ, McEvoy M, Attia J, Holliday EG, Montgomery GW, Martin NG, Nyholt DR, Henders AK, Hopper JL, Traficante N, AOCS GroupRuebner 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 PD, Dunning AM, Tomlinson I, Dowsett M, Easton DF, Spurdle AB - Endocr. Relat. Cancer (2015)

Bottom Line: SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Public Health and Primary CareCentre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, Cambridge CB1 8RN, UKDepartment of Genetics and Computational BiologyQIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, AustraliaWellcome Trust Centre for Human GeneticsUniversity of Oxford, Oxford OX3 7BN, UKAcademic Department of BiochemistryRoyal Marsden Hospital, London SW3 6JJ, UKDepartment of Clinical GeneticsSt George's Hospital Medical School, London SW17 0RE, UKDepartment of OncologyCentre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UKDepartment of Medical Epidemiology and BiostatisticsKarolinska Institutet, Stockholm SE-171 77, SwedenDepartment of MedicineDivision of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USADepartment of Gynecology and ObstetricsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyInstitute of Human GeneticsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyGynaecology Research UnitHannover Medical School, Hannover 30625, GermanyClinics of Gynaecology and ObstetricsHannover Medical School, Hannover 30625, GermanyDepartment of GynaecologyJena University Hospital - Friedrich Schiller University, Jena 07743, GermanyVesalius Research CenterLeuven 3000, BelgiumLaboratory for Translational GeneticsDepartment of Oncology, University Hospitals Leuven, Leuven 3000, BelgiumDepartment of Obstetrics and GynecologyDivision of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Leuven 3000, BelgiumDepartment of Health Sciences ResearchMayo Clinic, Rochester, Minnesota 55905, USADepartment of BiostatisticsUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USADepartment of Obstetrics and GynecologyDivision of G

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The observed and predicted risks of endometrial cancer associated with each rs727479 A allele. The Observed per-A allele OR is that observed in this study of 6608 and 37 925 endometrial cancer cases and controls. The predicted per-A allele OR is estimated based on the observed association between rs727479 and E2 levels in 2767 healthy post-menopausal women, and on the endometrial cancer OR associated with a doubling of post-menopausal E2 levels reported by Lukanova et al. (2004).
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fig4: The observed and predicted risks of endometrial cancer associated with each rs727479 A allele. The Observed per-A allele OR is that observed in this study of 6608 and 37 925 endometrial cancer cases and controls. The predicted per-A allele OR is estimated based on the observed association between rs727479 and E2 levels in 2767 healthy post-menopausal women, and on the endometrial cancer OR associated with a doubling of post-menopausal E2 levels reported by Lukanova et al. (2004).

Mentions: Following a Mendelian randomization argument, if elevated E2 concentration were causally associated with endometrial cancer (as opposed to an association produced by confounding), then we would expect any SNP which raises E2 to be proportionally associated with endometrial cancer. We observed an rs727429 per-A-allele increase in adjusted E2 concentration of 10% (95% CI=6–14%, from the regression coefficient in Table 1 for log-transformed levels). Lukanova et al. (2004) estimated that the odds ratio for endometrial cancer associated with a doubling of post-menopausal E2 concentration was 2.06 (CI=1.47–2.89; it was necessary to use an external estimate because hormone levels had only been measured in control subjects in our study). Based on this published estimate, the predicted per-allele OR for endometrial cancer would be 1.09 (CI=1.03–1.21), which is consistent with that observed in our study (OR=1.15, CI=1.11–1.21) (Fig. 4).


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)Gorman M, Martin L, Hodgson S, National Study of Endometrial Cancer Genetics Group (NSECG)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 HM, Ashton K, Proietto T, Otton G, Carvajal-Carmona L, Tham E, Liu T, Mints M, for RENDOCASScott RJ, McEvoy M, Attia J, Holliday EG, Montgomery GW, Martin NG, Nyholt DR, Henders AK, Hopper JL, Traficante N, AOCS GroupRuebner 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 PD, Dunning AM, Tomlinson I, Dowsett M, Easton DF, Spurdle AB - Endocr. Relat. Cancer (2015)

The observed and predicted risks of endometrial cancer associated with each rs727479 A allele. The Observed per-A allele OR is that observed in this study of 6608 and 37 925 endometrial cancer cases and controls. The predicted per-A allele OR is estimated based on the observed association between rs727479 and E2 levels in 2767 healthy post-menopausal women, and on the endometrial cancer OR associated with a doubling of post-menopausal E2 levels reported by Lukanova et al. (2004).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697192&req=5

fig4: The observed and predicted risks of endometrial cancer associated with each rs727479 A allele. The Observed per-A allele OR is that observed in this study of 6608 and 37 925 endometrial cancer cases and controls. The predicted per-A allele OR is estimated based on the observed association between rs727479 and E2 levels in 2767 healthy post-menopausal women, and on the endometrial cancer OR associated with a doubling of post-menopausal E2 levels reported by Lukanova et al. (2004).
Mentions: Following a Mendelian randomization argument, if elevated E2 concentration were causally associated with endometrial cancer (as opposed to an association produced by confounding), then we would expect any SNP which raises E2 to be proportionally associated with endometrial cancer. We observed an rs727429 per-A-allele increase in adjusted E2 concentration of 10% (95% CI=6–14%, from the regression coefficient in Table 1 for log-transformed levels). Lukanova et al. (2004) estimated that the odds ratio for endometrial cancer associated with a doubling of post-menopausal E2 concentration was 2.06 (CI=1.47–2.89; it was necessary to use an external estimate because hormone levels had only been measured in control subjects in our study). Based on this published estimate, the predicted per-allele OR for endometrial cancer would be 1.09 (CI=1.03–1.21), which is consistent with that observed in our study (OR=1.15, CI=1.11–1.21) (Fig. 4).

Bottom Line: SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Public Health and Primary CareCentre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, Cambridge CB1 8RN, UKDepartment of Genetics and Computational BiologyQIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, AustraliaWellcome Trust Centre for Human GeneticsUniversity of Oxford, Oxford OX3 7BN, UKAcademic Department of BiochemistryRoyal Marsden Hospital, London SW3 6JJ, UKDepartment of Clinical GeneticsSt George's Hospital Medical School, London SW17 0RE, UKDepartment of OncologyCentre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UKDepartment of Medical Epidemiology and BiostatisticsKarolinska Institutet, Stockholm SE-171 77, SwedenDepartment of MedicineDivision of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USADepartment of Gynecology and ObstetricsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyInstitute of Human GeneticsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyGynaecology Research UnitHannover Medical School, Hannover 30625, GermanyClinics of Gynaecology and ObstetricsHannover Medical School, Hannover 30625, GermanyDepartment of GynaecologyJena University Hospital - Friedrich Schiller University, Jena 07743, GermanyVesalius Research CenterLeuven 3000, BelgiumLaboratory for Translational GeneticsDepartment of Oncology, University Hospitals Leuven, Leuven 3000, BelgiumDepartment of Obstetrics and GynecologyDivision of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Leuven 3000, BelgiumDepartment of Health Sciences ResearchMayo Clinic, Rochester, Minnesota 55905, USADepartment of BiostatisticsUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USADepartment of Obstetrics and GynecologyDivision of G

No MeSH data available.


Related in: MedlinePlus