Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

Abstract

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29). Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

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Item Type:	Article
Authors/Creators:	Johnson, N. Dudbridge, F. Orr, N. Gibson, L. Jones, M.E. Schoemaker, M.J. Folkerd, E.J. Haynes, B.P. Hopper, J.L. Southey, M.C. Dite, G.S. Apicella, C. Schmidt, M.K. Broeks, A. Van't Veer, L.J. Atsma, F. Muir, K. Lophatananon, A. Fasching, P.A. Beckmann, M.W. Ekici, A.B. Renner, S.P. Sawyer, E. Tomlinson, I. Kerin, M. Miller, N. Burwinkel, B. Marme, F. Schneeweiss, A. Sohn, C. Guenel, P. Truong, T. Cordina, E. Menegaux, F. Bojesen, S.E. Nordestgaard, B.G. Flyger, H. Milne, R. Zamora, M.P. Arias Perez, J.I. Benitez, J. Bernstein, L. Anton-Culver, H. Ziogas, A. Dur, C.C. Brenner, H. Mueller, H. Arndt, V. Dieffenbach, A.K. Meindl, A. Heil, J. Bartram, C.R. Schmutzler, R.K. Brauch, H. Justenhoven, C. Ko, Y-D. Nevanlinna, H. Muranen, T.A. Aittomaeki, K. Blomqvist, C. Matsuo, K. Doerk, T. Bogdanova, NV. Antonenkova, N.N. Lindblom, A. Mannermaa, A. Kataja, V. Kosma, V-M. Hartikainen, J.M. Chenevix-Trench, G. Beesley, J. Wu, A.H. Van den Berg, D. Tseng, C-C. Lambrechts, D. Smeets, D. Neven, P. Wildiers, H. Chang-Claude, J. Rudolph, A. Nickels, S. Flesch-Janys, D. Radice, P. Peterlongo, P. Bonanni, B. Pensotti, V. Couch, F.J. Olson, J.E. Wang, X. Fredericksen, Z. Pankratz, V.S. Giles, G.G. Severi, G. Baglietto, L. Haiman, C. Simard, J. Goldberg, M.S. Labreche, F. Dumont, M. Soucy, P. Teo, S. Yip, C.H. Phuah, S.Y. Cornes, B.K. Kristensen, V.N. Alnaes, G.G. Borresen-Dale, A-L. Zheng, W. Winqvist, R. Pylkaes, K. Jukkola-Vuorinen, A. Grip, M. Andrulis, I.L Knight, J.A. Glendon, G. Mulligan, A.M. Devillee, P. Figueroa, J. Chanock, S.J. Lissowska, J. Sherman, M.E. Hall, P. Schoof, N. Hooning, M. Hollestelle, A. Oldenburg, R.A. Tilanus-Linthorst, M. Liu, J. Cox, A. Brock, I.W. Reed, M.W.R. Cross, S.S. https://orcid.org/0000-0003-2044-1754 Blot, W. Signorello, L.B. Pharoah, P.D.P. Dunning, A.M. Shah, M. Kang, D. Noh, D-Y. Park, S.K. Choi, J-Y. Hartman, M. Miao, H. Lim, W.Y. Tang, A. Hamann, U. Foersti, A. Ruediger, T. Ulmer, H.U. Jakubowska, A. Lubinski, J. Jaworska-Bieniek, K. Durda, K. Sangrajrang, S. Gaborieau, V. Brennan, P. Mckay, J. Slager, S. Toland, A.E. Vachon, C. Yannoukakos, D. Shen, C-Y. Yu, J-C. Huang, C-S. Hou, M-F. Gonzalez-Neira, A. Tessier, D.C. Vincent, D. Bacot, F. Luccarini, C. Dennis, J. Michailidou, K. Bolla, M.K. Wang, J. Easton, D.F. Garcia-Closas, M. Dowsett, M. Ashworth, A. Swerdlow, A.J. Peto, J. Silva, I.D.S. Fletcher, O. Breast, G.E.I. Investigators, K. Grp, AOCS
Copyright, Publisher and Additional Information:	© 2014 Johnson et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Dates:	Published: 26 May 2014 Accepted: 24 April 2014
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	13 Apr 2016 10:37
Last Modified:	13 Apr 2016 10:37
Published Version:	http://dx.doi.org/10.1186/bcr3662
Status:	Published
Publisher:	BioMed Central
Refereed:	Yes
Identification Number:	10.1186/bcr3662
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:97450

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Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

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