DataSheet_3_Deciphering the causal association and co-disease mechanisms between psoriasis and breast cancer.docx

BackgroundPrior research has indicated a link between psoriasis and the susceptibility to breast cancer (BC); however, a definitive causal relationship remains elusive. This study sought to elucidate the causal connection and shared underlying mechanisms between psoriasis and BC through bidirectional Mendelian randomization (MR) and bioinformatic approaches.
MethodsWe employed a bidirectional MR approach to examine the potential causal connection between psoriasis and BC. Genetic data pertaining to psoriasis and BC were sourced from extensive published genome-wide association studies. The inverse -variance weighted or wald ratio served as the primary method for estimating causal effects. Sensitivity analysis of the MR results was applied with multiple methods. Leveraged datasets from the Gene Expression Omnibus and the Cancer Genome Atlas repositories to identify common differentially expressed genes, shedding light on the shared mechanisms underlying these two conditions.
ResultsThe MR analysis revealed that when considering psoriasis as an exposure factor, the incidences of BC (OR=1.027) and estrogen receptor negative (ER-) BC (OR=1.054) were higher than in the general population. When using Her2+ BC as an exposure factor, the risk of psoriasis was 0.822 times higher (OR=0.822) than in the general population. Sensitivity analysis indicated that the results were robust. Transcriptome analysis showed that CXCL13 and CCL20 were activated in both BC and psoriasis. Both diseases were also linked to neutrophil chemotaxis, the IL-17 pathway, and the chemokine pathway.
ConclusionThe results suggest that psoriasis may increase the risk of BC, especially ER- BC, while reverse MR suggests a decreased risk of psoriasis in Her2+ BC. Transcriptome analysis revealed a shared mechanism between psoriasis and BC.

背景 既往研究已表明银屑病（psoriasis）与乳腺癌（breast cancer, BC）的易感性存在关联，但二者间确切的因果关系仍未明确。本研究采用双向孟德尔随机化（Mendelian randomization, MR）与生物信息学方法，旨在阐明银屑病与乳腺癌之间的因果联系及共同潜在发病机制。
方法 本研究借助双向孟德尔随机化方法，探究银屑病与乳腺癌之间潜在的因果关联。银屑病与乳腺癌的遗传数据均来源于已发表的大规模全基因组关联研究（genome-wide association studies）。因果效应估计的核心方法为逆方差加权法或瓦尔德比率法。本研究采用多种分析手段对MR结果开展敏感性验证，以确保研究结论的稳健性。此外，我们利用基因表达综合数据库（Gene Expression Omnibus, GEO）与癌症基因组图谱（Cancer Genome Atlas, TCGA）的公开数据集，筛选两种疾病共有的差异表达基因，以揭示二者共同的潜在发病机制。
结果 MR分析结果显示，以银屑病作为暴露因素时，乳腺癌（比值比OR=1.027）及雌激素受体阴性（estrogen receptor negative, ER-）乳腺癌（OR=1.054）的发病率均高于普通人群。以人类表皮生长因子受体2阳性（Her2+）乳腺癌作为暴露因素时，银屑病的发病风险为普通人群的0.822倍（OR=0.822）。敏感性分析结果表明本次研究结论具有良好的稳健性。转录组分析显示，CXCL13与CCL20在乳腺癌与银屑病中均被激活。此外，两种疾病均与中性粒细胞趋化、IL-17信号通路及趋化因子信号通路密切相关。
结论 本研究结果提示，银屑病可能会升高乳腺癌的发病风险，尤其是ER-乳腺癌；而反向MR分析则表明，Her2+乳腺癌患者的银屑病发病风险有所降低。转录组分析结果揭示了银屑病与乳腺癌之间存在共同的发病机制。