AbstractIntroductionWe examined the association between mammographic density and single-nucleotide polymorphisms (SNPs) in genes encoding CYP1A1, CYP1B1, aromatase, 17β-HSD, ESR1, and ESR2 in pre- and early perimenopausal white, African-American, Chinese, and Japanese women.MethodsThe Study of Women's Health Across the Nation is a longitudinal community-based cohort study. We analyzed data from 451 pre- and early perimenopausal participants of the ancillary SWAN Mammographic Density study for whom we had complete information regarding mammographic density, genotypes, and covariates. With multivariate linear regression, we examined the relation between percentage mammographic breast density (outcome) and each SNP (primary predictor), adjusting for age, race/ethnicity, parity, cigarette smoking, and body mass index (BMI).ResultsAfter multivariate adjustment, theCYP1B1rs162555 CC genotype was associated with a 9.4% higher mammographic density than the TC/TT genotype (P= 0.04). TheCYP19A1rs936306 TT genotype was associated with 6.2% lower mammographic density than the TC/CC genotype (P= 0.02). The positive association betweenCYP1A1rs2606345 and mammographic density was significantly stronger among participants with BMI greater than 30 kg/m2than among those with BMI less than 25 kg/m2(Pinteraction= 0.05). Among white participants, theESR1rs2234693 CC genotype was associated with a 7.0% higher mammographic density than the CT/TT genotype (P= 0.01).ConclusionsSNPs in certain genes encoding sex steroid metabolism enzymes and ESRs were associated with mammographic density. Because the encoded enzymes and ESR1 are expressed in breast tissue, these SNPs may influence breast cancer risk by altering mammographic density.