激素代谢途径基因多态性、绝经激素治疗与乳腺癌风险的关联：加利福尼亚教师研究队列中的巢式病例对照研究。
The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort.
机构信息
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
出版信息
Breast Cancer Res. 2011 Apr 1;13(2):R37. doi: 10.1186/bcr2859.
INTRODUCTION
The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy.
METHODS
We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT).
RESULTS
The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT = 0.002; overall PACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women.
CONCLUSIONS
We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT.
简介
女性性激素雌激素和孕激素在乳腺癌的发病机制中起着重要作用。因此，参与这些激素代谢的基因发生变异可能会影响乳腺癌的风险，而这些关联可能因绝经状态和激素治疗的使用而有所不同，这似乎是合理的。
方法
我们在加利福尼亚教师研究队列中进行了一项乳腺癌的巢式病例对照研究。我们分析了 24 个激素途径基因中的 317 个标记单核苷酸多态性（SNP），共涉及 2746 名非西班牙裔白人妇女：1351 例病例和 1395 例对照。通过拟合条件逻辑回归模型，使用所有妇女或根据绝经状态和激素治疗使用定义的妇女亚组来估计比值比（OR）和 95％置信区间（CI）。调整了多重相关检验（PACT）的 P 值。
结果
与 SLCO1B1 中的 SNP 观察到最强的关联，SLCO1B1 是一种溶质载体有机阴离子转运蛋白基因，将雌二醇-17β-葡糖苷酸和雌酮-3-硫酸盐从血液转运到肝细胞中。SLCO1B1 的 38 个标记 SNP 中有 10 个与绝经后乳腺癌风险显著相关；5 个 SNP（rs11045777、rs11045773、rs16923519、rs4149057、rs11045884）在该基因内进行多重测试调整后仍具有统计学意义（PACT = 0.019-0.046）。在入组时正在使用雌孕激素联合治疗（EPT）的绝经后妇女中，SLCO1B1 中 rs4149013 的每个次要等位基因的乳腺癌风险比为 2.31（95％CI = 1.47-3.62）（P = 0.0003; 基因内 PACT = 0.002; 总体 PACT = 0.023）。在本研究中评估的其他激素途径基因中的 SNP 与绝经前或绝经后妇女的乳腺癌风险无关。
结论
我们发现证据表明，SLCO1B1 中的遗传变异与绝经后妇女的乳腺癌风险相关，尤其是在使用 EPT 的妇女中。
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