Mammographic density and candidate gene variants: a twins and sisters study.
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 Asn(367)Thr 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.


CONCLUSIONS
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.
Stone
Jennifer
J
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, 2/723 Swanston Street, Carlton, Victoria 3053, Australia.
Gurrin
Lyle C
LC
Byrnes
Graham B
GB
Schroen
Christopher J
CJ
Treloar
Susan A
SA
Padilla
Emma J D
EJ
Dite
Gillian S
GS
Southey
Melissa C
MC
Hayes
Vanessa M
VM
Hopper
John L
JL
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D008327:Mammography; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D035781:Siblings; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D015096:3-Hydroxysteroid Dehydrogenases; D002394:Catechol O-Methyltransferase; D004268:DNA-Binding Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D051759:Xeroderma Pigmentosum Group D Protein; C515497:IGFBP3 protein, human; C110901:X-ray repair cross complementing protein 3; C508053:ERBB2 protein, human; C497292:ERCC2 protein, human