Yi Junyu, Chen Qingfeng, Liu Xiaoyi, Mao Yan, Wang Yongmei, Lv Meng, Wang Haibo, Wang Yuanyuan
Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People's Republic of China.
Sci Rep. 2025 Apr 28;15(1):14892. doi: 10.1038/s41598-025-99410-0.
This study uses Mendelian randomization (MR) to investigate the causal roles of CD40 and CD40L in BC.Data from genome-wide association studies (GWAS) on BC (overall, ER-positive, and ER-negative subtypes) and CD40/CD40L levels were obtained from the IEU database. Causal associations were assessed using the inverse-variance weighted (IVW) method, with additional robustness checks performed via MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran's Q test and MR-PRESSO, were conducted to assess heterogeneity and pleiotropy. Reverse MR analyses were also performed to examine if BC influences CD40/CD40L levels.A borderline significant association was found between CD40 levels and overall BC risk (IVW OR 1.027, 95% CI 1.000-1.054, p = 0.049), with a more robust association observed for ER-positive BC (OR 1.048, 95% CI 1.016-1.082, p = 0.003). No significant associations were found between CD40 levels and ER-negative BC. CD40L did not show any significant associations with BC. Reverse MR analysis indicated no causal effect of BC on CD40/CD40L levels. CD40 is causally associated with a borderline increase in overall BC risk and a more significant increase in ER-positive BC risk. These findings suggest a potential role for CD40 in BC, particularly in ER-positive cases.
本研究采用孟德尔随机化（MR）方法来探究CD40和CD40L在乳腺癌（BC）中的因果作用。从IEU数据库获取了关于乳腺癌（总体、雌激素受体阳性和雌激素受体阴性亚型）以及CD40/CD40L水平的全基因组关联研究（GWAS）数据。使用逆方差加权（IVW）方法评估因果关联，并通过MR-Egger、加权中位数和加权模式方法进行额外的稳健性检验。进行了敏感性分析，包括 Cochr an's Q检验和MR-PRESSO，以评估异质性和多效性。还进行了反向MR分析，以检验乳腺癌是否会影响CD40/CD40L水平。结果发现CD40水平与总体乳腺癌风险之间存在边缘显著关联（IVW优势比1.027，95%置信区间1.000 - 1.054，p = 0.049），对于雌激素受体阳性乳腺癌观察到更强健的关联（优势比1.048，95%置信区间1.016 - 1.082，p = 0.003）。未发现CD40水平与雌激素受体阴性乳腺癌之间存在显著关联。CD40L与乳腺癌未显示出任何显著关联。反向MR分析表明乳腺癌对CD40/CD40L水平无因果效应。CD40与总体乳腺癌风险的边缘性增加以及雌激素受体阳性乳腺癌风险的更显著增加存在因果关联。这些发现表明CD40在乳腺癌中具有潜在作用，尤其是在雌激素受体阳性病例中。
