Sex steroid metabolism polymorphisms and mammographic density in pre- and early perimenopausal women

Carolyn J Crandall,Lesley M Butler,Maryfran R Sowers,Janet S Sinsheimer,Sybil L Crawford,Laurel A Habel,Mary E Sehl,Gail A Greendale,Ellen B Gold

doi:10.1186/bcr2340

Abstract

IntroductionWe 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, the CYP1B1 rs162555 CC genotype was associated with a 9.4% higher mammographic density than the TC/TT genotype (P = 0.04). The CYP19A1 rs936306 TT genotype was associated with 6.2% lower mammographic density than the TC/CC genotype (P = 0.02). The positive association between CYP1A1 rs2606345 and mammographic density was significantly stronger among participants with BMI greater than 30 kg/m2 than among those with BMI less than 25 kg/m2 (Pinteraction = 0.05). Among white participants, the ESR1 rs2234693 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.

Highlights

We examined the association between mammographic density and single-nucleotide polymorphisms (SNPs) in genes encoding CYP1A1, CYP1B1, aromatase, 17βHSD, ESR1, and ESR2 in pre- and early perimenopausal white, African-American, Chinese, and Japanese women
Single-nucleotide polymorphisms (SNPs) in certain genes encoding sex steroid metabolism enzymes and estrogen receptors (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

Summary

Introduction

We examined the association between mammographic density and single-nucleotide polymorphisms (SNPs) in genes encoding CYP1A1, CYP1B1, aromatase, 17βHSD, ESR1, and ESR2 in pre- and early perimenopausal white, African-American, Chinese, and Japanese women. The presence of sex steroid metabolic enzymes and ESRs in breast tissue [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24] suggests that local activation of estrogen to potentially reactive metabolites within breast tissue may play a role in initiating and promoting carcinogenesis [18] Such enzymes include CYP1A1, CYP1B1, and 17βhydroxysteroid dehydrogenase (17β-HSD). Single-nucleotide polymorphisms (SNPs) in genes encoding sex steroid-metabolizing enzymes or receptors have effects on the hormonal milieu of the breast and on levels of potential mammary carcinogens [6]

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