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Mammographic Density and Candidate Gene Variants: A Twins and Sisters Study

¹ Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology and ² Genetic Epidemiology Laboratory, University of Melbourne, Melbourne, Victoria, Australia; ³ Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia; and ⁴ Garvan Institute of Medical Research, Cancer Research Program, and ⁵ Department of Medicine, St. Vincent's Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia

Requests for reprints: John Hopper, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, 2/723 Swanston Street, Carlton, Victoria 3053, Australia. Phone: 61-0383440697; Fax: 61-0393495815. E-mail: j.hopper{at}unimelb.edu.au

Background: Mammographic density, the light/white radiographic appearance on a mammogram that represents connective and epithelial tissue, is a strong risk factor for breast cancer which seems to be highly heritable. Little is known about its genetic determinants.

Methods: We studied 457 women from 207 sisterhoods (104 monozygotic twins, 182 dizygotic twins, and 171 singletons). Percentage mammographic density (PMD) as well as dense area and nondense area were calculated using a computer-assisted method. We measured six single nucleotide polymorphisms from six candidate genes (COMT, HSD3B1, IGFBP3, HER2, XPD, and XRCC3). Associations between genotypes and mammographic measures were tested (a) cross-sectionally using a multivariate normal model fitted using FISHER that allowed separate correlations for monozygotic, dizygotic, and nontwin pairs and (b) within sister pairs using paired t tests.

Results: Cross-sectionally, each additional copy of the HSD3B1 Asn³⁶⁷Thr variant allele was associated with lower PMD (–3.47% per allele; SE = 1.65; P = 0.035). Within-pair regression estimates confirmed this association. There was no evidence for an association between the mammographic density measures and any of the other variants studied.

Conclusion: We have replicated an association between a variant in the HSD3B1 gene and PMD, which suggests that HSD3B1 may be genetic determinant of mammographic density. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1479–84)

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