Limits...
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

No MeSH data available.


Related in: MedlinePlus

Association of SNPs in the CYP19A1 region with (A) endometrial cancer and (B) E2:T, highlighting rs727479. Each point indicates the statistical significance of the association between a SNP and endometrial cancer (Fig. 2A) or between a SNP and the E2:T ratio (Fig. 2B). Squares denote SNPs directly genotyped by the iCOGS array; circles are SNPs for which genotypes were imputed. The larger purple square is rs727479, the SNP with the strongest evidence of association with endometrial cancer. Other colours show the strength of linkage disequilibrium between each SNP with rs7277479.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4697192&req=5

fig2: Association of SNPs in the CYP19A1 region with (A) endometrial cancer and (B) E2:T, highlighting rs727479. Each point indicates the statistical significance of the association between a SNP and endometrial cancer (Fig. 2A) or between a SNP and the E2:T ratio (Fig. 2B). Squares denote SNPs directly genotyped by the iCOGS array; circles are SNPs for which genotypes were imputed. The larger purple square is rs727479, the SNP with the strongest evidence of association with endometrial cancer. Other colours show the strength of linkage disequilibrium between each SNP with rs7277479.

Mentions: Combining results across the four studies, 171 SNPs had P<1×10−4, compared with an expected number of less than one under the hypothesis (Supplementary Table 2, see section on supplementary data given at the end of this article). Fifty SNPs were significant at the conventional GWAS threshold of 5×10−8, of which rs727479 in intron 2 was the most significantly associated (OR per A allele=1.15, CI=1.11–1.21, P=4.81×10−11, Table 1, Fig. 2A). This SNP was directly genotyped in all four studies, and the strength of the association did not differ among studies (I2=0.0%, Phet=0.92). (Supplementary Table 2, see section on supplementary data given at the end of this article, Supplementary Fig. 1A). Conditioning on rs727479, no other SNPs reached P<10−4 (Supplementary Table 2).


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 SNPs in the CYP19A1 region with (A) endometrial cancer and (B) E2:T, highlighting rs727479. Each point indicates the statistical significance of the association between a SNP and endometrial cancer (Fig. 2A) or between a SNP and the E2:T ratio (Fig. 2B). Squares denote SNPs directly genotyped by the iCOGS array; circles are SNPs for which genotypes were imputed. The larger purple square is rs727479, the SNP with the strongest evidence of association with endometrial cancer. Other colours show the strength of linkage disequilibrium between each SNP with rs7277479.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Association of SNPs in the CYP19A1 region with (A) endometrial cancer and (B) E2:T, highlighting rs727479. Each point indicates the statistical significance of the association between a SNP and endometrial cancer (Fig. 2A) or between a SNP and the E2:T ratio (Fig. 2B). Squares denote SNPs directly genotyped by the iCOGS array; circles are SNPs for which genotypes were imputed. The larger purple square is rs727479, the SNP with the strongest evidence of association with endometrial cancer. Other colours show the strength of linkage disequilibrium between each SNP with rs7277479.
Mentions: Combining results across the four studies, 171 SNPs had P<1×10−4, compared with an expected number of less than one under the hypothesis (Supplementary Table 2, see section on supplementary data given at the end of this article). Fifty SNPs were significant at the conventional GWAS threshold of 5×10−8, of which rs727479 in intron 2 was the most significantly associated (OR per A allele=1.15, CI=1.11–1.21, P=4.81×10−11, Table 1, Fig. 2A). This SNP was directly genotyped in all four studies, and the strength of the association did not differ among studies (I2=0.0%, Phet=0.92). (Supplementary Table 2, see section on supplementary data given at the end of this article, Supplementary Fig. 1A). Conditioning on rs727479, no other SNPs reached P<10−4 (Supplementary Table 2).

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