Research article
Genetic variation in the estrogen metabolic pathway and mammographic density as an intermediate phenotype of breast cancer
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* Corresponding author: Jingmei Li Jingmei.Li@ki.se
1 Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Box 281, 171 77 Stockholm, Sweden
2 Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
3 Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
4 Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
5 Program in Genetic and Molecular Epidemiology, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
6 Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
7 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
8 Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, 75 Mikras Asias Str, Goudi, Athens 115 27, Greece
Breast Cancer Research 2010, 12:R19 doi:10.1186/bcr2488
Published: 9 March 2010Abstract
Introduction
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.