title: Genetic variation in the estrogen metabolic pathway and mammographic density as an intermediate phenotype of breast cancer.
abstract: BACKGROUND
  Several studies have examined the effect of genetic variants in genes involved in the estrogen metabolic pathway on mammographic density, but the number of loci studied and the sample sizes evaluated have been small and pathways have not been evaluated comprehensively. In this study, we evaluate the association between mammographic density and genetic variants of the estrogen metabolic pathway.
  
  
  METHODS
  A total of 239 SNPs in 34 estrogen metabolic genes were studied in 1,731 Swedish women who participated in a breast cancer case-control study, of which 891 were cases and 840 were controls. Film mammograms of the medio-lateral oblique view were digitalized and the software Cumulus was used for computer-assisted semi-automated thresholding of mammographic density. Generalized linear models controlling for possible confounders were used to evaluate the effects of SNPs on mammographic density. Results found to be nominally significant were examined in two independent populations. The admixture maximum likelihood-based global test was performed to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three subpathways for androgen synthesis, androgen-to-estrogen conversion and estrogen removal.
  
  
  RESULTS
  Genetic variants of genes involved in estrogen metabolism exhibited no appreciable effect on mammographic density. None of the nominally significant findings were validated. In addition, global analyses on the overall estrogen metabolic pathway and its subpathways did not yield statistically significant results.
  
  
  CONCLUSIONS
  Overall, there is no conclusive evidence that genetic variants in genes involved in the estrogen metabolic pathway are associated with mammographic density in postmenopausal women.
authors.affiliation: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden. Jingmei.Li@ki.se
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.forename: Louise
authors.initials: L
authors.lastname: Eriksson
authors.forename: Keith
authors.initials: K
authors.lastname: Humphreys
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Scott
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.forename: Per
authors.initials: P
authors.lastname: Hall
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D008327:Mammography / Q000379:methods*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D004967:Estrogens