title: Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.
abstract: Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown.
  
  
  
  We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol.
  
  
  
  We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17β-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype.
  
  
  
  Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. frnfje@ous-hf.no.|Institute of Clinical Medicine, University of Oslo, Oslo, N-0316, Norway. frnfje@ous-hf.no.
authors.forename: F N
authors.initials: FN
authors.lastname: Fjeldheim
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Frydenberg
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway.
authors.forename: V G
authors.initials: VG
authors.lastname: Flote
authors.affiliation: Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: McTiernan
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037, Tromsø, Norway.|Department of Microbiology and Infection Control, University Hospital of North Norway, 9038, Tromsø, Norway.
authors.forename: A-S
authors.initials: AS
authors.lastname: Furberg
authors.affiliation: Department of Anthropology, Harvard University, 11 Divinity Avenue, Cambridge, MA, 02138, USA.
authors.forename: P T
authors.initials: PT
authors.lastname: Ellison
authors.affiliation: Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Barrett
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Wilsgaard
authors.affiliation: Department of Environmental Health, Institute of Public Health, Jagiellonian University Medical College, Grzegorzecka 20, Krakow, 31-351, Poland.
authors.forename: G
authors.initials: G
authors.lastname: Jasienska
authors.affiliation: Cancer Registry of Norway, PO Box 5313, Majorstuen, Oslo, N-0304, Norway.
authors.forename: G
authors.initials: G
authors.lastname: Ursin
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, N-0316, Norway.
authors.forename: E A
authors.initials: EA
authors.lastname: Wist
authors.affiliation: The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway.|Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
authors.forename: I
authors.initials: I
authors.lastname: Thune
mesh_terms: D000328:Adult; D000483:Alleles; D000071060:Breast Density; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000235:genetics*; D004967:Estrogens / Q000097:blood*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008597:Menstrual Cycle; D009664:Norway; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012463:Saliva; D013997:Time Factors
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D004958:Estradiol
keywords: 17β-estradiol; ESR1; Mammographic density; Polymorphisms; Premenopausal