Université Laval, Département de médecine sociale et préventive, Quebec City, QC, Canada.
BMC Cancer. 2010 Nov 22;10:636. doi: 10.1186/1471-2407-10-636.
Single nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway appear to be associated with breast cancer risk and possibly with mammographic density (MD), but little is known of these associations among premenopausal women. This study examines the association of 11 polymorphisms in five estrogen-related genes (estrogen receptors alpha and beta (ERα, ERβ), 17β-hydroxysteroid dehydrogenase 1 (HSD17B1), catechol-O-methyltransferase (COMT), cytochrome P450 1B1 (CYP1B1)) with premenopausal MD. Effect modification of four estrogen-related factors (parity, age at menarche, hormonal derivatives use and body mass index (BMI)) on this relation is also assessed.
Polymorphisms were genotyped in 741 premenopausal Caucasian women whose MD was measured in absolute density (AD, cm²) and percent density using a computer-assisted method. Multivariate linear models were used to examine the associations (P(trend)) and interactions (Pi).
None of the SNPs showed a statistically significant association with AD. However, each additional rare allele of rs1056836 CYP1B1 was associated with a reduction in AD among nulliparous women (P(trend) = 0.004), while no association was observed among parous women (P(trend) = 0.62; Pi = 0.02). An increase in the number of rare alleles of the HSD17B1 SNP (rs598126 and rs2010750) was associated with an increase in AD among women who never used hormonal derivatives (P(trend) = 0.06 and P(trend) = 0.04, respectively), but with a decrease in AD among past hormonal derivatives users (P(trend) = 0.04; Pi = 0.02 and P(trend) = 0.08; Pi = 0.01, respectively). Moreover, a negative association of rs598126 HSD17B1 SNP with AD was observed among women with higher BMI (>median) (P(trend) = 0.01; Pi = 0.02). A negative association between an increased number of rare alleles of COMT rs4680 SNP and AD was limited to women who never used hormonal derivatives (P(trend) = 0.02; Pi = 0.03) or with late age at menarche (>median) (P(trend) = 0.03; Pi = 0.02). No significant association was observed between polymorphisms in the ERα or ERβ genes and AD. Similar results, although less significant, were observed when MD was assessed in percent density.
SNPs located in CYP1B1, COMT or HSD17B1 genes seem to be associated with MD in some strata of estrogen-related factors. Our findings suggest that modifying effects of estrogen-related factors should be considered when evaluating associations of polymorphisms in estrogen-related genes with premenopausal mammographic density.
参与雌激素途径的基因中的单核苷酸多态性（SNPs）似乎与乳腺癌风险相关，并且可能与乳腺 X 线密度（MD）相关，但关于这些关联在绝经前妇女中的情况知之甚少。本研究探讨了五个与雌激素相关的基因（雌激素受体 alpha 和 beta（ERα、ERβ）、17β-羟甾脱氢酶 1（HSD17B1）、儿茶酚-O-甲基转移酶（COMT）、细胞色素 P450 1B1（CYP1B1））中的 11 个多态性与绝经前 MD 的关系。还评估了四个与雌激素相关的因素（生育次数、初潮年龄、激素衍生物使用和体重指数（BMI））对这种关系的效应修饰作用。
对 741 名绝经前白种女性的多态性进行基因分型，这些女性的 MD 使用计算机辅助方法以绝对密度（AD，cm²）和百分比密度进行测量。使用多元线性模型来检查关联（P（趋势））和相互作用（Pi）。
没有一个 SNP 与 AD 呈统计学显著关联。然而，CYP1B1 基因 rs1056836 的每个稀有等位基因的增加与未生育妇女的 AD 减少相关（P（趋势）= 0.004），而在生育妇女中则没有观察到这种关联（P（趋势）= 0.62；Pi = 0.02）。HSD17B1 基因 rs598126 和 rs2010750 的 SNP 稀有等位基因数量的增加与从不使用激素衍生物的女性的 AD 增加相关（P（趋势）分别为 0.06 和 0.04），但与过去使用激素衍生物的女性的 AD 减少相关（P（趋势）分别为 0.04；Pi = 0.02 和 P（趋势）= 0.08；Pi = 0.01）。此外，在 BMI 较高（>中位数）的女性中，HSD17B1 基因 rs598126 SNP 与 AD 呈负相关（P（趋势）= 0.01；Pi = 0.02）。COMT rs4680 SNP 稀有等位基因数量的增加与 AD 之间的负相关仅局限于从不使用激素衍生物的女性（P（趋势）= 0.02；Pi = 0.03）或初潮年龄较晚（>中位数）的女性（P（趋势）= 0.03；Pi = 0.02）。在 ERα 或 ERβ 基因中的多态性与 AD 之间未观察到显著关联。当 MD 以百分比密度评估时，观察到类似的结果，尽管不太显著。
位于 CYP1B1、COMT 或 HSD17B1 基因中的 SNP 似乎与某些雌激素相关因素的 MD 相关。我们的研究结果表明，在评估雌激素相关基因中的多态性与绝经前乳腺 X 线密度的关联时，应考虑雌激素相关因素的修饰作用。
