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Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

¹ Department of Preventive Medicine, University of Southern California, Los Angeles, California; ² Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; ³ Cancer Research United Kingdom, Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom; ⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; ⁵ American Cancer Society, Atlanta, Georgia; ⁶ Broad Institute of Harvard and MIT, Cambridge, Massachusetts; ⁷ Public Health Institute of Navarra, Pamplona, Spain; ⁸ Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany; ⁹ Division of Preventive Medicine, ¹⁰ Channing Laboratory, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School and ¹¹ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; ¹² Institut National de la Sante et de la Recherche Medicale, Institut Gustave Roussy, Villejuif, France; ¹³ Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii; ¹⁴ Department of Radiation Sciences/Oncology, Umeå University, Umeå, Sweden; ¹⁵ Institute of Community Medicine University of Tromsø, Tromsø, Norway; ¹⁶ Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy; ¹⁷ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; ¹⁸ Imperial College, London, United Kingdom; ¹⁹ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; ²⁰ Cancer Research United Kingdom Epidemiology Unit, University of Oxford, Oxford, United Kingdom; and ²¹ Department of Hygiene and Epidemiology, School of Medicine, University of Athens, Athens, Greece

Requests for reprints: Christopher A. Haiman, Department of Preventive Medicine, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, MS 44, Room 4441, Los Angeles, CA 90033-0800. Phone: 323-865-0429; Fax: 323-865-0127; E-mail: haiman{at}usc.edu.

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 (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. [Cancer Res 2007;67(5):1893–7]

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