观察性研究已报道系统性红斑狼疮（SLE）与常见女性激素依赖性癌症相关，但其潜在的因果关系仍未确定。本研究旨在通过曼德利安随机化分析（MR分析）探索这些疾病之间的因果关联。我们从欧洲和东亚人群的全基因组关联研究（GWAS）中选择SLE的工具变量。从相应的族群GWAS中获取女性恶性肿瘤的遗传变异。我们采用倒数方差加权（IVW）作为主要分析方法，随后进行敏感性分析。此外，我们进行多变量MR（MVMR）以调整身体质量指数和雌二醇的直接影响。最后，我们实施了反向MR分析，并给出了一个负面例子，以测试MR结果的可靠性。我们发现，在欧洲人群中，SLE与总体子宫内膜癌风险呈显著负相关（比值比[OR] =0.961，95％置信区间[CI]=0.935-0.987，P=3.57E-03），并且中等程度地负相关于内膜型子宫内膜癌（ENEC）（OR = 0.965，95％CI = 0.936-0.995，P = 0.024）风险。我们使用其他MR模型复制了这些结果，并通过MVMR检测到直接作用（总体子宫内膜癌，OR=0.962，95％CI=0.941-0.983，P=5.11E-04；ENEC，OR=0.964，95％CI=0.940-0.989，P=0.005）。此外，我们揭示SLE与东亚人群中乳腺癌风险降低相关（OR = 0.951，95％CI = 0.918-0.986，P = 0.006），并且该效应在MVMR中仍然显著（OR = 0.934，95% CI = 0.859-0.976，P = 0.002）。正态MR结果的统计功效均> 0.9。这一发现表明，MR分析可能存在SLE与欧洲和东亚人群中总体子宫内膜癌和乳腺癌风险之间的因果作用，从而弥补了观察研究本质上的局限性。版权所有© 2023年中国医师协会，由Wolters Kluwer，Inc.在CC-BY-NC-ND许可下生产。

Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis.We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results.We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P = 0.002). The statistical powers of positive MR results were all >0.9.This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.