Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
PLoS One. 2012;7(9):e44308. doi: 10.1371/journal.pone.0044308. Epub 2012 Sep 6.
Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.
We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.
We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity.
We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.
真核染色体末端的端粒在维持基因组的完整性和稳定性方面起着关键作用，并参与 DNA 损伤/修复反应的启动。
我们进行了一项病例对照研究，以评估先前发现与乳腺癌风险显著相关的端粒维持基因中的三个单核苷酸多态性（TERT-07、TERT-54 和 POT1-03）的作用。我们使用来自乳腺癌家族登记处（BCFR）纽约站点的姐妹对进行研究。在 313 对姐妹对中，有 333 例乳腺癌病例和 409 例未受影响的姐妹纳入了本研究。我们分别应用条件逻辑回归和广义估计方程（GEE）模型来评估姐妹对中三个 SNP 与乳腺癌风险之间的关联。我们使用 GEE 模型检查了基因型、协变量与未受影响姐妹中端粒体长度之间的关联。
我们没有发现端粒维持基因中的三个 SNP 与乳腺癌风险之间存在显著关联，无论是通过条件逻辑回归还是 GEE 模型，这些 SNP 也与端粒体长度没有显著关联。在未受影响的姐妹中，较短的端粒体与从未使用激素替代疗法（HRT）显著相关。HRT 使用时间的延长与端粒体长度的缩短显著相关。在调整了献血年龄、种族和民族后，从未使用 HRT 的端粒体长度平均值为 0.77（SD=0.35），HRT 使用<5 年的端粒体长度平均值为 0.67（SD=0.29），HRT 使用≥5 年的端粒体长度平均值为 0.59（SD=0.24）。
我们发现外源性激素暴露与端粒体长度呈负相关。没有观察到遗传变异与端粒体长度或乳腺癌风险之间存在显著关联。这些发现为了解激素暴露在端粒体长度和乳腺癌风险调节中的作用提供了初步证据，但需要在前瞻性研究中进行复制。
