Abstract：
OBJECTIVE: The causal relationship between breast cancer and its estrogen receptor (ER) subtypes and neutropenia and agranulocytosis is unclear.
METHODS: In two-sample Mendelian randomization (MR), we used inverse variance weighting (IVW), Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods to analyze causality for ER-positive breast cancer, ER-negative breast cancer, overall breast cancer, and drug-induced neutropenia and agranulocytosis. To validate the results, we performed the analysis again using GWAS data on neutropenia from different databases. In multivariable MR (MVMR), we assessed the independent effects of ER-positive and ER-negative breast cancer on causality.
RESULTS: Two-sample MR analysis showed a causal relationship between ER-positive breast cancer (IVW odds ratio (OR) = 1.319, P = 7.580 × 10-10), ER-negative breast cancer (OR = 1.285, P = 1.263 × 10-4), overall breast cancer (OR = 1.418, P = 2.123 × 10-13), and drug-induced neutropenia and a causal relationship between ER-positive breast cancer (OR = 1.349, P = 1.402 × 10-7), ER-negative breast cancer (OR = 1.235, P = 7.615 × 10-3), overall breast cancer (OR = 1.429, P = 9.111 × 10-10), and neutropenia. Similarly, ER-positive breast cancer (OR = 1.213, P = 5.350 × 10-8), ER-negative breast cancer (OR = 1.179, P = 1.300 × 10-3), and overall breast cancer (OR = 1.275, P = 8.642 × 10-11) also had a causal relationship with agranulocytosis. MVMR analysis showed that ER-positive breast cancer remained causally associated with drug-induced neutropenia (OR = 1.233, P = 4.188 × 10-4), neutropenia (OR = 1.283, P = 6.363 × 10-4), and agranulocytosis (OR = 1.142, P = 4.549 × 10-3). Heterogeneity analysis and pleiotropy test showed that our results were reliable.
CONCLUSIONS: Our study provides genetic evidence for a causal association between breast cancer and its estrogen receptor subtypes and neutropenia. In clinical practice, in addition to focusing on therapeutic factors, additional attention should be given to breast cancer patients to avoid severe neutropenia.
METHODS: In two-sample Mendelian randomization (MR), we used inverse variance weighting (IVW), Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods to analyze causality for ER-positive breast cancer, ER-negative breast cancer, overall breast cancer, and drug-induced neutropenia and agranulocytosis. To validate the results, we performed the analysis again using GWAS data on neutropenia from different databases. In multivariable MR (MVMR), we assessed the independent effects of ER-positive and ER-negative breast cancer on causality.
RESULTS: Two-sample MR analysis showed a causal relationship between ER-positive breast cancer (IVW odds ratio (OR) = 1.319, P = 7.580 × 10-10), ER-negative breast cancer (OR = 1.285, P = 1.263 × 10-4), overall breast cancer (OR = 1.418, P = 2.123 × 10-13), and drug-induced neutropenia and a causal relationship between ER-positive breast cancer (OR = 1.349, P = 1.402 × 10-7), ER-negative breast cancer (OR = 1.235, P = 7.615 × 10-3), overall breast cancer (OR = 1.429, P = 9.111 × 10-10), and neutropenia. Similarly, ER-positive breast cancer (OR = 1.213, P = 5.350 × 10-8), ER-negative breast cancer (OR = 1.179, P = 1.300 × 10-3), and overall breast cancer (OR = 1.275, P = 8.642 × 10-11) also had a causal relationship with agranulocytosis. MVMR analysis showed that ER-positive breast cancer remained causally associated with drug-induced neutropenia (OR = 1.233, P = 4.188 × 10-4), neutropenia (OR = 1.283, P = 6.363 × 10-4), and agranulocytosis (OR = 1.142, P = 4.549 × 10-3). Heterogeneity analysis and pleiotropy test showed that our results were reliable.
CONCLUSIONS: Our study provides genetic evidence for a causal association between breast cancer and its estrogen receptor subtypes and neutropenia. In clinical practice, in addition to focusing on therapeutic factors, additional attention should be given to breast cancer patients to avoid severe neutropenia.
摘要：
目的：乳腺癌及其雌激素受体（ER）亚型与中性粒细胞减少和粒细胞缺乏之间的因果关系尚不清楚。
方法：在双样本孟德尔随机化(MR)中，我们使用方差逆加权(IVW)，贝叶斯加权MR(BWMR)，MR-Egger,加权中位数，简单模式，和加权模式方法分析ER阳性乳腺癌的因果关系，ER阴性乳腺癌,整体乳腺癌，以及药物诱导的中性粒细胞减少和粒细胞缺乏症。为了验证结果，我们再次使用来自不同数据库的中性粒细胞减少的GWAS数据进行分析.在多变量MR(MVMR)中，我们评估了ER阳性和ER阴性乳腺癌对因果关系的独立影响.
结果：双样本MR分析显示ER阳性乳腺癌之间存在因果关系（IVW比值比（OR）=1.319，P=7.580×10-10），ER阴性乳腺癌(OR=1.285,P=1.263×10-4),整体乳腺癌（OR=1.418，P=2.123×10-13），和药物诱导的中性粒细胞减少与ER阳性乳腺癌之间的因果关系（OR=1.349，P=1.402×10-7），ER阴性乳腺癌(OR=1.235,P=7.615×10-3),整体乳腺癌（OR=1.429，P=9.111×10-10），和中性粒细胞减少症.同样，ER阳性乳腺癌(OR=1.213,P=5.350×10-8),ER阴性乳腺癌(OR=1.179,P=1.300×10-3),总体乳腺癌（OR=1.275，P=8.642×10-11）也与粒细胞缺乏有因果关系。MVMR分析显示ER阳性乳腺癌与药物性中性粒细胞减少有因果关系(OR=1.233,P=4.188×10-4)。中性粒细胞减少症(OR=1.283,P=6.363×10-4),粒细胞缺乏（OR=1.142，P=4.549×10-3）。异质性分析和多效性检验表明我们的结果是可靠的。
结论：我们的研究为乳腺癌及其雌激素受体亚型与中性粒细胞减少症之间的因果关系提供了遗传学证据。在临床实践中,除了关注治疗因素，应额外注意乳腺癌患者，以避免严重的中性粒细胞减少。
方法：在双样本孟德尔随机化(MR)中，我们使用方差逆加权(IVW)，贝叶斯加权MR(BWMR)，MR-Egger,加权中位数，简单模式，和加权模式方法分析ER阳性乳腺癌的因果关系，ER阴性乳腺癌,整体乳腺癌，以及药物诱导的中性粒细胞减少和粒细胞缺乏症。为了验证结果，我们再次使用来自不同数据库的中性粒细胞减少的GWAS数据进行分析.在多变量MR(MVMR)中，我们评估了ER阳性和ER阴性乳腺癌对因果关系的独立影响.
结果：双样本MR分析显示ER阳性乳腺癌之间存在因果关系（IVW比值比（OR）=1.319，P=7.580×10-10），ER阴性乳腺癌(OR=1.285,P=1.263×10-4),整体乳腺癌（OR=1.418，P=2.123×10-13），和药物诱导的中性粒细胞减少与ER阳性乳腺癌之间的因果关系（OR=1.349，P=1.402×10-7），ER阴性乳腺癌(OR=1.235,P=7.615×10-3),整体乳腺癌（OR=1.429，P=9.111×10-10），和中性粒细胞减少症.同样，ER阳性乳腺癌(OR=1.213,P=5.350×10-8),ER阴性乳腺癌(OR=1.179,P=1.300×10-3),总体乳腺癌（OR=1.275，P=8.642×10-11）也与粒细胞缺乏有因果关系。MVMR分析显示ER阳性乳腺癌与药物性中性粒细胞减少有因果关系(OR=1.233,P=4.188×10-4)。中性粒细胞减少症(OR=1.283,P=6.363×10-4),粒细胞缺乏（OR=1.142，P=4.549×10-3）。异质性分析和多效性检验表明我们的结果是可靠的。
结论：我们的研究为乳腺癌及其雌激素受体亚型与中性粒细胞减少症之间的因果关系提供了遗传学证据。在临床实践中,除了关注治疗因素，应额外注意乳腺癌患者，以避免严重的中性粒细胞减少。
