Flote Vidar G, Furberg Anne-Sofie, McTiernan Anne, Frydenberg Hanne, Ursin Giske, Iversen Anita, Lofteroed Trygve, Ellison Peter T, Wist Erik A, Egeland Thore, Wilsgaard Tom, Makar Karen W, Chang-Claude Jenny, Thune Inger
The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway.
Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037, Norway.
Breast Cancer Res. 2014 Dec 19;16(6):499. doi: 10.1186/s13058-014-0499-2.
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.
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.
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)).
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.
乳腺X线密度高是已确定的乳腺癌风险因素，循环雌激素在乳腺癌发展过程中影响雌激素调节基因的表达。然而，关于绝经前女性细胞色素P450 19A1（CYP19A1）基因常见变异、雌激素每日水平、乳腺X线密度表型和体重指数（BMI）之间的相互关系，人们了解较少。
基于与雌激素途径相关的合理生物学机制，我们在202名绝经前女性中研究了CYP19A1单核苷酸多态性（SNP）、17β-雌二醇与乳腺X线密度之间的关联。使用Illumina Golden Gate平台对DNA进行基因分型。在整个月经周期中测量每日唾液中17β-雌二醇浓度。使用计算机辅助方法（Madena）评估乳腺X线密度表型。我们使用多变量线性和逻辑回归模型确定关联。
rs749292的次要等位基因与每日17β-雌二醇呈正相关（P = 0.026），rs7172156的次要等位基因与每日17β-雌二醇呈负相关（P = 0.002）。我们观察到，与主要基因型AA相比，rs7172156次要基因型为aa的体重较重女性（BMI>23.6 kg/m²）在整个月经周期中每日17β-雌二醇水平低87%。此外，rs749292次要等位基因与绝对乳腺X线密度呈负相关（P = 0.032）。携带rs749292次要等位基因的瘦女性发生高绝对乳腺X线密度（>32.4 cm²）的风险降低70%至80%；杂合子Aa：比值比（OR）= 0.23（95%置信区间0.07至0.75）。rs7172156次要纯合基因型的瘦女性发生高绝对乳腺X线密度的OR为5.45（aa：OR = 5.45（95%置信区间1.13至26.3））。
我们的研究结果表明，CYP19A1基因中的两个SNP，即rs749292和rs7172156，与每日雌激素水平和乳腺X线密度表型均相关。BMI可能会改变这些关联，但需要更大规模的研究。
