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. 2014 Dec 19;16(6):499.
doi: 10.1186/s13058-014-0499-2.

Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women

Vidar G Flote  1 , Anne-Sofie Furberg  2 , Anne McTiernan  3 , Hanne Frydenberg  4 , Giske Ursin  5 , Anita Iversen  6 , Trygve Lofteroed  7 , Peter T Ellison  8 , Erik A Wist  9 , Thore Egeland  10 , Tom Wilsgaard  11 , Karen W Makar  12 , Jenny Chang-Claude  13 , Inger Thune  14   15
Affiliations

Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women

Vidar G Flote et al. Breast Cancer Res. .

Abstract

Introduction: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women.

Methods: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models.

Results: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)).

Conclusion: Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.

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Figures

Figure 1
Figure 1
Mean salivary 17β-estradiol levels across menstrual cycles for rs749292 and rs7172156 , adjusted for age, body mass index and parity. (a) rs749292 mean estradiol levels: minor homozygous genotype (aa) (n = 46), 19.8 pmol/L; heterozygous genotype (Aa) (n = 86), 18.7 pmol/L; and major homozygous genotype (AA) (n = 57), 16.0 pmol/L (P = 0.075). (b) rs749292 and low body mass index (BMI ≤23.6 kg/m2): aa (n = 25), 17.5 pmol/L; Aa (n = 46), 17.4 pmol/L; and AA (n = 25), 14.7 pmol/L (P = 0.294). (c) rs749292 and high BMI >23.6 kg/m2: aa (n = 21), 22.3 pmol/L; Aa (n = 40), 19.9 pmol/L; and AA (n = 30), 17.6 pmol/L (P = 0.265). (d) rs7172156 mean estradiol levels: aa (n = 29), 12.3 pmol/L; Aa (n = 83), 19.2 pmol/L; and AA (n = 78), 19.3 pmol/L (P = 0.001). (e) rs7172156 and low BMI ≤23.6 kg/m2: aa (n = 12), 12.9 pmol/L; Aa (n = 41), 17.5 pmol/L; and AA (n = 45), 16.9 pmol/L (P = 0.208). (f) rs7172156 and high BMI >23.6 kg/m2: aa (n = 17), 12.0 pmol/L; Aa (n = 42), 20.9 pmol/L; and AA (n = 33), 22.4 pmol/L (P = 0.001).
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