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Abstract：
BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.
METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.
RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.
CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.
RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.
CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
摘要：
背景：更年期激素治疗（MHT），缓解更年期症状的常用治疗方法，与结直肠癌（CRC）的风险较低有关。通知CRC风险预测和MHT风险效益评估，我们旨在评估CRC多基因风险评分(PRS)和MHT对CRC风险的联合关联.
方法：我们使用了来自欧洲血统的28,486名绝经后妇女（11,519例和16,967名对照）的数据。基于141个CRC相关遗传变异的PRS被建模为四分位数的分类变量。使用逻辑回归评估PRS和MHT使用之间的乘法相互作用。使用归因于相互作用的相对过量风险(RERI)测量加性相互作用。根据MHT使用和PRS计算50岁女性的30年累积CRC风险。
结果：与PRS最低四分位数的女性相比，PRS最高四分位数的女性使用MHT的比值比降低更大（p值=2.7×10-8）。在PRS的最高四分位数，在统计学上，接受任何MHT的女性的30年CRC风险显着低于不接受任何MHT的女性，3.7%（3.3%-4.0%）对6.1%（5.7%-6.5%）（差异2.4%，P值=1.83×10-14）；这些差异也具有统计学意义，但在PRS最低四分位数中的幅度较小，1.6%(1.4%-1.8%)对2.2%(1.9%-2.4%)(差异0.6%，P值=1.01×10-3)，表明与遗传CRC风险的最低四分位数相比，与最高的任何MHT使用相关的绝对风险降低了4倍。
结论：使用MHT对遗传风险较高的女性降低CRC风险具有更大的影响。这些发现对CRC风险预测模型的开发以及在MHT使用的风险收益评估中考虑遗传信息具有潜在意义。
方法：我们使用了来自欧洲血统的28,486名绝经后妇女（11,519例和16,967名对照）的数据。基于141个CRC相关遗传变异的PRS被建模为四分位数的分类变量。使用逻辑回归评估PRS和MHT使用之间的乘法相互作用。使用归因于相互作用的相对过量风险(RERI)测量加性相互作用。根据MHT使用和PRS计算50岁女性的30年累积CRC风险。
结果：与PRS最低四分位数的女性相比，PRS最高四分位数的女性使用MHT的比值比降低更大（p值=2.7×10-8）。在PRS的最高四分位数，在统计学上，接受任何MHT的女性的30年CRC风险显着低于不接受任何MHT的女性，3.7%（3.3%-4.0%）对6.1%（5.7%-6.5%）（差异2.4%，P值=1.83×10-14）；这些差异也具有统计学意义，但在PRS最低四分位数中的幅度较小，1.6%(1.4%-1.8%)对2.2%(1.9%-2.4%)(差异0.6%，P值=1.01×10-3)，表明与遗传CRC风险的最低四分位数相比，与最高的任何MHT使用相关的绝对风险降低了4倍。
结论：使用MHT对遗传风险较高的女性降低CRC风险具有更大的影响。这些发现对CRC风险预测模型的开发以及在MHT使用的风险收益评估中考虑遗传信息具有潜在意义。
