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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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Association of SNP rs727479 with (A) endometrial cancer and (B) E2 levels, by quartile of BMI distribution. In Fig. 3A the log(OR) of endometrial cancer associated with each A allele of SNP rs727479 is shown for each quartile of the BMI distribution, adjusting for age. There is a borderline significant interaction between genotype and BMI quartile (P=0.047). Figure 3B shows the regression coefficient (β) for the association between each A allele of rs727479 and log-transformed E2 levels (adjusted for laboratory batch, study, age at blood draw, BMI, HRT use and menopausal status), (Pinteraction=0.066). For both plots, the error bars are 95% CI, and the quartiles are based on the BMI distribution in endometrial cancer cases, to allow for comparability between plots, and to ensure sufficient cases in each quartile.
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fig3: Association of SNP rs727479 with (A) endometrial cancer and (B) E2 levels, by quartile of BMI distribution. In Fig. 3A the log(OR) of endometrial cancer associated with each A allele of SNP rs727479 is shown for each quartile of the BMI distribution, adjusting for age. There is a borderline significant interaction between genotype and BMI quartile (P=0.047). Figure 3B shows the regression coefficient (β) for the association between each A allele of rs727479 and log-transformed E2 levels (adjusted for laboratory batch, study, age at blood draw, BMI, HRT use and menopausal status), (Pinteraction=0.066). For both plots, the error bars are 95% CI, and the quartiles are based on the BMI distribution in endometrial cancer cases, to allow for comparability between plots, and to ensure sufficient cases in each quartile.

Mentions: BMI was available for 2858 cases and 14 098 controls from the iCOGS studies. As expected, BMI was positively associated with endometrial cancer risk (OR=1.60 (1.54–1.66) per quartile, P<10−100). SNP rs727479 was not associated with BMI in previous analyses (P=0.94 in the >230 000 GIANT consortium participants (Locke et al. 2015))_ENREF_24 nor in the iCOGS controls (P=0.31). There was evidence of a stronger disease association for rs727479 among women with higher BMI (interaction P=0.034, which was slightly attenuated when adjusted for age, P=0.047), with the strongest association among women in the highest quartile (OR=1.25 (1.05–1.49), P=0.012, adjusting for age), (Table 1, Fig. 3A).


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)

Association of SNP rs727479 with (A) endometrial cancer and (B) E2 levels, by quartile of BMI distribution. In Fig. 3A the log(OR) of endometrial cancer associated with each A allele of SNP rs727479 is shown for each quartile of the BMI distribution, adjusting for age. There is a borderline significant interaction between genotype and BMI quartile (P=0.047). Figure 3B shows the regression coefficient (β) for the association between each A allele of rs727479 and log-transformed E2 levels (adjusted for laboratory batch, study, age at blood draw, BMI, HRT use and menopausal status), (Pinteraction=0.066). For both plots, the error bars are 95% CI, and the quartiles are based on the BMI distribution in endometrial cancer cases, to allow for comparability between plots, and to ensure sufficient cases in each quartile.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Association of SNP rs727479 with (A) endometrial cancer and (B) E2 levels, by quartile of BMI distribution. In Fig. 3A the log(OR) of endometrial cancer associated with each A allele of SNP rs727479 is shown for each quartile of the BMI distribution, adjusting for age. There is a borderline significant interaction between genotype and BMI quartile (P=0.047). Figure 3B shows the regression coefficient (β) for the association between each A allele of rs727479 and log-transformed E2 levels (adjusted for laboratory batch, study, age at blood draw, BMI, HRT use and menopausal status), (Pinteraction=0.066). For both plots, the error bars are 95% CI, and the quartiles are based on the BMI distribution in endometrial cancer cases, to allow for comparability between plots, and to ensure sufficient cases in each quartile.
Mentions: BMI was available for 2858 cases and 14 098 controls from the iCOGS studies. As expected, BMI was positively associated with endometrial cancer risk (OR=1.60 (1.54–1.66) per quartile, P<10−100). SNP rs727479 was not associated with BMI in previous analyses (P=0.94 in the >230 000 GIANT consortium participants (Locke et al. 2015))_ENREF_24 nor in the iCOGS controls (P=0.31). There was evidence of a stronger disease association for rs727479 among women with higher BMI (interaction P=0.034, which was slightly attenuated when adjusted for age, P=0.047), with the strongest association among women in the highest quartile (OR=1.25 (1.05–1.49), P=0.012, adjusting for age), (Table 1, Fig. 3A).

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