Article open access publication

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Endocrine Related Cancer, Bioscientifica, ISSN 1479-6821

Volume 23, 2, 2015

DOI:10.1530/erc-15-0386, Dimensions: pub.1014339541, PMC: PMC4697192, PMID: 26574572,

Authors

Hall, Per (6)
Zhao, Hui (12) (13)
Depreeuw, Jeroen (12) (13)
Salvesen, Helga B (16) (17)
Trovik, Jone (16) (17)
Ashton, Katie (18) (19) (20)
Liu, Tao (6)
Mints, Miriam (6) (23)
Scott, Rodney J (18) (19) (20)
Attia, John (18) (20)
Nyholt, Dale R (2) (24)
Burwinkel, Barbara (27) (28)
Brauch, Hiltrud (28) (30) (31)
Giles, Graham G (25) (32) (33)
Kristensen, Vessela N (34) (35) (36)
Wang, Qin (1)
Bojesen, Stig E (38) (39)

Affiliations

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  1. (1) University of Cambridge, grid.5335.0
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) Wellcome Centre for Human Genetics, grid.270683.8
  4. (4) Royal Marsden Hospital, grid.424926.f
  5. (5) St George's, University of London, grid.264200.2
  6. (6) Karolinska Institute, grid.4714.6
  7. (7) University of California, Los Angeles, grid.19006.3e
  8. (8) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
  9. (9) Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
  10. (10) Hannover Medical School, grid.10423.34
  11. (11) Friedrich Schiller University Jena, grid.9613.d
  12. (12) Universitair Ziekenhuis Leuven, grid.410569.f
  13. (13) Vesalius Research Center, Leuven, 3000, Belgium
  14. (14) Mayo Clinic, grid.66875.3a
  15. (15) University of Kansas Medical Center, grid.412016.0
  16. (16) Haukeland University Hospital, grid.412008.f
  17. (17) University of Bergen, grid.7914.b
  18. (18) University of Newcastle Australia, grid.266842.c
  19. (19) School of Biomedical Sciences and Pharmacy, University of Newcastle Newcastle, Newcastle, New South Wales, 2308, Australia
  20. (20) John Hunter Hospital, grid.414724.0
  21. (21) University of California, Davis, grid.27860.3b
  22. (22) University of Tolima, grid.412192.d
  23. (23) Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, SE-171 77, Sweden
  24. (24) Queensland University of Technology, grid.1024.7
  25. (25) University of Melbourne, grid.1008.9
  26. (26) Institute of Cancer Research, grid.18886.3f
  27. (27) Heidelberg University, grid.7700.0
  28. (28) German Cancer Research Center, grid.7497.d
  29. (29) Technical University of Munich, grid.6936.a
  30. (30) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  31. (31) University of Tübingen, grid.10392.39
  32. (32) Cancer Council Victoria, grid.3263.4
  33. (33) Monash University, grid.1002.3
  34. (34) Akershus University Hospital, grid.411279.8
  35. (35) Faculty of Medicine, The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316, Norway
  36. (36) Oslo University Hospital, grid.55325.34
  37. (37) University of Sheffield, grid.11835.3e
  38. (38) Herlev Hospital, grid.411900.d, Capital Region
  39. (39) University of Copenhagen, grid.5254.6, KU

Description

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.

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Times Cited: 31

Field Citation Ratio (FCR): 6.83

Relative Citation ratio (RCR): 1.94

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