Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women |
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Authors: | Haiman Christopher A Dossus Laure Setiawan V Wendy Stram Daniel O Dunning Alison M Thomas Gilles Thun Michael J Albanes Demetrius Altshuler David Ardanaz Eva Boeing Heiner Buring Julie Burtt Noël Calle Eugenia E Chanock Stephen Clavel-Chapelon Françoise Colditz Graham A Cox David G Feigelson Heather Spencer Hankinson Susan E Hayes Richard B Henderson Brian E Hirschhorn Joel N Hoover Robert Hunter David J Kaaks Rudolf Kolonel Laurence N Le Marchand Loïc Lenner Per Lund Eiliv Panico Salvatore Peeters Petra H Pike Malcolm C Riboli Elio Tjonneland Anne Travis Ruth Trichopoulos Dimitrios |
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Institution: | Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. haiman@usc.edu |
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Abstract: | The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (> or =5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 x 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer. |
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