title: Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women.
abstract: BACKGROUND
  High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women.
  
  
  METHODS
  Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models.
  
  
  RESULTS
  The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)).
  
  
  CONCLUSIONS
  Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. v.g.flote@medisin.uio.no.
authors.forename: Vidar G
authors.initials: VG
authors.lastname: Flote
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037, Norway. anne-sofie.furberg@uit.no.
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Furberg
authors.affiliation: Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA, 98109-1024, USA. amctiern@fhcrc.org.
authors.forename: Anne
authors.initials: A
authors.lastname: McTiernan
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. hanne.frydenberg@medisin.uio.no.
authors.forename: Hanne
authors.initials: H
authors.lastname: Frydenberg
authors.affiliation: Cancer Registry of Norway, PO Box 5313, Majorstuen, Oslo, N-0304, Norway. giske.ursin@kreftregisteret.no.
authors.forename: Giske
authors.initials: G
authors.lastname: Ursin
authors.affiliation: Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037, Norway. anita.iversen@uit.no.
authors.forename: Anita
authors.initials: A
authors.lastname: Iversen
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. loftry@ous-hf.no.
authors.forename: Trygve
authors.initials: T
authors.lastname: Lofteroed
authors.affiliation: Department of Anthropology, Harvard University, Cambridge, MA, 02138, USA. pellison@fas.harvard.edu.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Ellison
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. erik.wist@medisin.uio.no.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Wist
authors.affiliation: Department of Chemistry, Norwegian University of Life Sciences, Biotechnology and Food Science, Aas, N-1432, Norway. thore.egeland@nmbu.no.
authors.forename: Thore
authors.initials: T
authors.lastname: Egeland
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037, Norway. tom.wilsgaard@uit.no.
authors.forename: Tom
authors.initials: T
authors.lastname: Wilsgaard
authors.affiliation: Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA, 98109-1024, USA. kmakar@fhcrc.org.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Unit of Genetic Epidemiology, Division of Cancer Epidemiology, Deutches Krebsforschungszentrum, 69120, Heidelberg, Germany. j.chang-claude@dkfz-heidelberg.de.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. inger.thune@uit.no.|Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037, Norway. inger.thune@uit.no.
authors.forename: Inger
authors.initials: I
authors.lastname: Thune
mesh_terms: D000328:Adult; D001141:Aromatase / Q000235:genetics*; D015992:Body Mass Index; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017697:Premenopause
chemical_list: D004958:Estradiol; D001141:Aromatase; C561410:CYP19A1 protein, human