Does circulating progesterone mediate the associations of single nucleotide polymorphisms in progesterone receptor (PGR)-related genes with mammographic breast density in premenopausal women?
Does circulating progesterone mediate the associations of single nucleotide polymorphisms in progesterone receptor (PGR)-related genes with mammographic breast density in premenopausal women?
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DOI：
10.1007/s12672-021-00438-1
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发表时间：
2021
影响因子：
2.2
通讯作者：
Toriola AT
中科院分区：
文献类型：
--
作者：
Akinjiyan FA;Han Y;Luo J;Toriola AT
孕激素是乳腺中的一种增殖激素，但在绝经前妇女中，孕酮调节途径中的遗传变异与乳房X线摄影乳腺密度（MD）的相关性以及这些相关性是否通过循环孕酮介导尚不清楚。因此，我们在364名绝经前妇女中调查了这些相关性，平均年龄为44岁。我们测序了179个孕酮受体（PGR）相关的单核苷酸多态性（SNP）。我们使用Volpara测量体积百分比密度（VPD）和非致密体积（NDV）。分别对循环孕酮或VPD/NDV进行线性回归模型拟合。我们进行了介导分析，以评估SNP对VPD/NDV的影响是否通过循环孕酮介导。所有分析均针对混杂因素、月经周期阶段进行调整，并应用Benjamini-Hochberg错误发现（FDR）调整的p值来校正多重检验。在多变量分析中，只有PGR rs657516对VPD有直接影响，（平均直接效应估计值= − 0.20，95%CI = − 0.38 ~ − 0.04，p值= 0.02），但在FDR校正后，这在统计学上并不显著，且该效应并非由循环孕酮介导（两种基因型的平均中介效应= 0.01，95%CI =-0.02 ~0.03，p值= 0.70）。5个SNPs（PGR rs 11571241、rs 11571239、rs 1824128、rs 11571150、PGRMC 1 rs 41294894）与循环孕酮相关，但在FDR校正后，这些均无统计学显著性。PGR相关基因中的SNPs与VPD、NDV无关，循环孕酮也不介导这种关联，这表明这些SNPs对MD的影响（如果有的话）与循环孕酮无关。在线版本包含补充材料，可通过10.1007/s12672-021-00438-1获得。
Progesterone is a proliferative hormone in the breast but the associations of genetic variations in progesterone-regulated pathways with mammographic breast density (MD) in premenopausal women and whether these associations are mediated through circulating progesterone are not clearly defined. We, therefore, investigated these associations in 364 premenopausal women with a median age of 44 years. We sequenced 179 progesterone receptor (PGR)-related single nucleotide polymorphisms (SNPs). We measured volumetric percent density (VPD) and non-dense volume (NDV) using Volpara. Linear regression models were fit on circulating progesterone or VPD/NDV separately. We performed mediation analysis to evaluate whether the effect of a SNP on VPD/NDV is mediated through circulating progesterone. All analyses were adjusted for confounders, phase of menstrual cycle and the Benjamini–Hochberg false discovery (FDR) adjusted p-value was applied to correct for multiple testing. In multivariable analyses, only PGR rs657516 had a direct effect on VPD (averaged direct effect estimate = − 0.20, 95%CI = − 0.38 ~ − 0.04, p-value = 0.02) but this was not statistically significant after FDR correction and the effect was not mediated by circulating progesterone (mediation effect averaged across the two genotypes = 0.01, 95%CI = − 0.02 ~ 0.03, p-value = 0.70). Five SNPs (PGR rs11571241, rs11571239, rs1824128, rs11571150, PGRMC1 rs41294894) were associated with circulating progesterone but these were not statistically significant after FDR correction. SNPs in PGR-related genes were not associated with VPD, NDV and circulating progesterone did not mediate the associations, suggesting that the effects, if any, of these SNPs on MD are independent of circulating progesterone. The online version contains supplementary material available at 10.1007/s12672-021-00438-1.