Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan Hospital, The Third Affiliated Hospital of Kunming Medical University & Yunnan Cancer Hospital, Kunming, 650118, China.
Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
Sci Rep. 2024 Nov 19;14(1):28579. doi: 10.1038/s41598-024-79521-w.
There may be potential associations between various pathogens, antibody immune responses, and breast cancer (BC), but the specific mechanisms and causal relationships remain unclear.
First, multiple Mendelian randomization (MR) methods were used for univariable MR analysis to explore potential causal relationships between 34 antibody immune responses (related to 12 pathogens), 46 antibody immune responses (related to 13 pathogens), antibody responses post-COVID-19 vaccination, 731 immune cell types, and various BC subtypes (including overall BC, ER-positive, ER-negative, Luminal A, Luminal B, Luminal B HER2-negative, HER2-positive, and triple-negative BC). The primary results were then subjected to reverse MR analysis, heterogeneity testing using Cochran's Q, and horizontal pleiotropy testing. Robust findings were further used to design mediation pathways involving antibody immune responses, immune cells, and BC. After adjusting the effect estimates using multivariable MR (MVMR), a two-step mediation analysis was conducted to explore mediation pathways and mediation proportions. Finally, linkage disequilibrium score regression (LDSC) was applied to analyze the genetic correlation between phenotypes along mediation pathways, and cross-phenotype association analysis (CPASSOC) was performed to identify pleiotropic SNPs among three phenotypes along these pathways. Bayesian colocalization tests were conducted on pleiotropic SNPs using the multiple-trait-coloc (moloc).
We identified potential causal relationships between 15 antibody immune responses to 8 pathogens (Hepatitis B virus, Herpes Simplex Virus 2, Human Herpesvirus 6, Polyomavirus 2, BK polyomavirus, Cytomegalovirus, Helicobacter pylori, Chlamydia trachomatis), 250 immune cell phenotypes, and various BC subtypes. MVMR-adjusted mediation analysis revealed four potential mediation pathways. LDSC results showed no significant genetic correlation between phenotypes pairwise. CPASSOC analysis identified two potential mediation pathways with common pleiotropic SNPs (rs12121677, rs281378, rs2894250). However, none of these SNPs passed the Bayesian colocalization test by moloc. These results excluded horizontal pleiotropy, stabilizing MR analysis results.
This study utilized MR methods to analyze potential causal relationships between various antibody immune responses, immune cell types, and BC subtypes, identifying four potential regulatory mediation pathways. The findings of this study offer potential targets and research directions for virus-related and immunotherapy-related studies, providing a certain level of theoretical support. However, limitations such as GWAS sample size constraints and unclear specific pathophysiological mechanisms need further improvement and validation in future studies.
各种病原体、抗体免疫反应与乳腺癌（BC）之间可能存在潜在关联，但具体机制和因果关系尚不清楚。
首先，采用多种孟德尔随机化（MR）方法进行单变量 MR 分析，以探讨 34 种与 12 种病原体相关的抗体免疫反应、46 种与 13 种病原体相关的抗体免疫反应、COVID-19 疫苗接种后的抗体反应、731 种免疫细胞类型与各种 BC 亚型（包括总体 BC、ER 阳性、ER 阴性、Luminal A、Luminal B、Luminal B HER2 阴性、HER2 阳性和三阴性 BC）之间的潜在因果关系。然后，对主要结果进行反向 MR 分析、Cochran's Q 异质性检验和水平性多效性检验。稳健的结果进一步用于设计涉及抗体免疫反应、免疫细胞和 BC 的中介途径。使用多变量 MR（MVMR）调整效应估计值后，进行两步中介分析以探索中介途径和中介比例。最后，应用连锁不平衡得分回归（LDSC）分析沿中介途径的表型之间的遗传相关性，并使用跨表型关联分析（CPASSOC）识别这些途径中三种表型之间的多效性 SNP。使用多性状 colocalization（moloc）对多效性 SNP 进行贝叶斯共定位检验。
我们确定了与 8 种病原体（乙型肝炎病毒、单纯疱疹病毒 2、人类疱疹病毒 6、多瘤病毒 2、BK 多瘤病毒、巨细胞病毒、幽门螺杆菌和沙眼衣原体）的 15 种抗体免疫反应、250 种免疫细胞表型和各种 BC 亚型之间的潜在因果关系。MVMR 调整后的中介分析揭示了四个潜在的中介途径。LDSC 结果表明，表型之间没有显著的遗传相关性。CPASSOC 分析确定了两个具有共同多效性 SNP（rs12121677、rs281378、rs2894250）的潜在中介途径。然而，这些 SNP 中没有一个通过 moloc 的贝叶斯共定位检验。这些结果排除了水平性多效性，稳定了 MR 分析结果。
本研究利用 MR 方法分析了各种抗体免疫反应、免疫细胞类型与 BC 亚型之间的潜在因果关系，确定了四个潜在的调节中介途径。本研究的结果为病毒相关和免疫治疗相关研究提供了潜在的靶点和研究方向，为相关研究提供了一定的理论支持。然而，GWAS 样本量限制和不明确定的具体病理生理机制等局限性需要在未来的研究中进一步改进和验证。
