title: Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women.
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.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. haiman@usc.edu
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Laure
authors.initials: L
authors.lastname: Dossus
authors.forename: V Wendy
authors.initials: VW
authors.lastname: Setiawan
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Eva
authors.initials: E
authors.lastname: Ardanaz
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Julie
authors.initials: J
authors.lastname: Buring
authors.forename: Noël
authors.initials: N
authors.lastname: Burtt
authors.forename: Eugenia E
authors.initials: EE
authors.lastname: Calle
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Graham A
authors.initials: GA
authors.lastname: Colditz
authors.forename: David G
authors.initials: DG
authors.lastname: Cox
authors.forename: Heather Spencer
authors.initials: HS
authors.lastname: Feigelson
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Per
authors.initials: P
authors.lastname: Lenner
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: Petra H
authors.initials: PH
authors.lastname: Peeters
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Anne
authors.initials: A
authors.lastname: Tjonneland
authors.forename: Ruth
authors.initials: R
authors.lastname: Travis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.forename: Regina G
authors.initials: RG
authors.lastname: Ziegler
mesh_terms: D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000209:etiology*; D016022:Case-Control Studies; D015331:Cohort Studies; D004967:Estrogens / Q000097:blood*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000097:blood; D012307:Risk Factors
chemical_list: D004967:Estrogens; D001141:Aromatase