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Abstract：
Breast cancer is a common cancer type that leads to cancer-related deaths among women. HER2-positive breast cancer, in particular, is associated with poor prognosis due to its high aggressiveness, increased risk of recurrence, and metastasis potential. Previous observational studies have explored potential associations between inflammatory cytokines and the risk of two breast cancer subtypes (HER2-positive and HER2-negative), but the results have been inconsistent. To further elucidate the causal relationship between inflammatory cytokines and the two breast cancer subtypes, we conducted a two-sample Mendelian randomization (MR) study.
We employed a two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) statistics. After obtaining instrumental variables, we conducted MR analyses using five different methods to ensure the reliability of our results. Additionally, we performed tests for heterogeneity and horizontal pleiotropy. Subsequently, we conducted a reverse MR study by reversing exposure and outcome variables.
Evidence from our IVW analysis revealed that genetically predicted levels of IL-5 [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.04-1.35, P = 0.012], IL-7 (OR: 1.11, 95% CI: 1.01-1.22, P = 0.037), and IL-16 (OR: 1.13, 95% CI: 1.02-1.25, P = 0.025) were associated with an increased risk of HER2-positive breast cancer. Conversely, IL-10 (OR: 1.14, 95% CI: 1.03-1.26, P = 0.012) was associated with an increased risk of HER2-negative breast cancer. These results showed no evidence of heterogeneity or horizontal pleiotropy (P > 0.05). Results from the reverse MR analysis indicated no potential causal association between breast cancer and inflammatory cytokines (P > 0.05).
Our findings demonstrate that IL-5, IL-7, and IL-16 are risk factors for HER2-positive breast cancer, with varying degrees of increased probability of HER2-positive breast cancer associated with elevated levels of these inflammatory cytokines. Conversely, IL-10 is a risk factor for HER2-negative breast cancer. Reverse studies have confirmed that breast cancer is not a risk factor for elevated levels of inflammatory cytokines. This series of results clarifies the causal relationship between different types of inflammatory cytokines and different subtypes of breast cancer. Based on this research, potential directions for the mechanism research of different inflammatory cytokines and different subtypes of breast cancer have been provided, and potential genetic basis for identifying and treating different subtypes of breast cancer have been suggested.
We employed a two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) statistics. After obtaining instrumental variables, we conducted MR analyses using five different methods to ensure the reliability of our results. Additionally, we performed tests for heterogeneity and horizontal pleiotropy. Subsequently, we conducted a reverse MR study by reversing exposure and outcome variables.
Evidence from our IVW analysis revealed that genetically predicted levels of IL-5 [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.04-1.35, P = 0.012], IL-7 (OR: 1.11, 95% CI: 1.01-1.22, P = 0.037), and IL-16 (OR: 1.13, 95% CI: 1.02-1.25, P = 0.025) were associated with an increased risk of HER2-positive breast cancer. Conversely, IL-10 (OR: 1.14, 95% CI: 1.03-1.26, P = 0.012) was associated with an increased risk of HER2-negative breast cancer. These results showed no evidence of heterogeneity or horizontal pleiotropy (P > 0.05). Results from the reverse MR analysis indicated no potential causal association between breast cancer and inflammatory cytokines (P > 0.05).
Our findings demonstrate that IL-5, IL-7, and IL-16 are risk factors for HER2-positive breast cancer, with varying degrees of increased probability of HER2-positive breast cancer associated with elevated levels of these inflammatory cytokines. Conversely, IL-10 is a risk factor for HER2-negative breast cancer. Reverse studies have confirmed that breast cancer is not a risk factor for elevated levels of inflammatory cytokines. This series of results clarifies the causal relationship between different types of inflammatory cytokines and different subtypes of breast cancer. Based on this research, potential directions for the mechanism research of different inflammatory cytokines and different subtypes of breast cancer have been provided, and potential genetic basis for identifying and treating different subtypes of breast cancer have been suggested.
摘要：
背景：乳腺癌是一种常见的癌症类型，可导致女性癌症相关死亡。HER2阳性乳腺癌,特别是,由于其高侵袭性，与不良预后相关，复发风险增加，和转移潜力。先前的观察性研究已经探索了炎症细胞因子与两种乳腺癌亚型（HER2阳性和HER2阴性）风险之间的潜在关联。但是结果不一致。为了进一步阐明炎症细胞因子与两种乳腺癌亚型之间的因果关系，我们进行了双样本孟德尔随机化(MR)研究.
方法：我们使用公开可用的全基因组关联研究（GWAS）统计进行了双样本双向MR分析。在获得工具变量后，我们使用5种不同的方法进行了MR分析,以确保结果的可靠性.此外,我们对异质性和水平多效性进行了测试.随后，我们通过逆转暴露量和结局变量进行了反向MR研究.
结果：我们IVW分析的证据表明，IL-5的遗传预测水平[比值比（OR）：1.18，95％置信区间（CI）：1.04-1.35，P=0.012]，IL-7（OR：1.11，95%CI：1.01-1.22，P=0.037），IL-16(OR:1.13,95%CI:1.02-1.25,P=0.025)与HER2阳性乳腺癌风险增加相关.相反，IL-10（OR：1.14，95％CI：1.03-1.26，P=0.012）与HER2阴性乳腺癌的风险增加相关。这些结果表明没有证据表明异质性或水平多效性（P>0.05）。反向MR分析结果显示乳腺癌与炎性细胞因子之间没有潜在的因果关系(P>0.05)。
结论：我们的研究结果表明，IL-5、IL-7和IL-16是HER2阳性乳腺癌的危险因素，与这些炎性细胞因子水平升高相关的HER2阳性乳腺癌的概率不同程度增加。相反，IL-10是HER2阴性乳腺癌的危险因素。反向研究已经证实乳腺癌不是炎性细胞因子水平升高的危险因素。这一系列结果阐明了不同类型的炎性细胞因子与不同亚型乳腺癌之间的因果关系。基于这项研究,为不同炎症因子和不同亚型乳腺癌的机制研究提供了潜在的方向,并提出了识别和治疗不同亚型乳腺癌的潜在遗传基础。
方法：我们使用公开可用的全基因组关联研究（GWAS）统计进行了双样本双向MR分析。在获得工具变量后，我们使用5种不同的方法进行了MR分析,以确保结果的可靠性.此外,我们对异质性和水平多效性进行了测试.随后，我们通过逆转暴露量和结局变量进行了反向MR研究.
结果：我们IVW分析的证据表明，IL-5的遗传预测水平[比值比（OR）：1.18，95％置信区间（CI）：1.04-1.35，P=0.012]，IL-7（OR：1.11，95%CI：1.01-1.22，P=0.037），IL-16(OR:1.13,95%CI:1.02-1.25,P=0.025)与HER2阳性乳腺癌风险增加相关.相反，IL-10（OR：1.14，95％CI：1.03-1.26，P=0.012）与HER2阴性乳腺癌的风险增加相关。这些结果表明没有证据表明异质性或水平多效性（P>0.05）。反向MR分析结果显示乳腺癌与炎性细胞因子之间没有潜在的因果关系(P>0.05)。
结论：我们的研究结果表明，IL-5、IL-7和IL-16是HER2阳性乳腺癌的危险因素，与这些炎性细胞因子水平升高相关的HER2阳性乳腺癌的概率不同程度增加。相反，IL-10是HER2阴性乳腺癌的危险因素。反向研究已经证实乳腺癌不是炎性细胞因子水平升高的危险因素。这一系列结果阐明了不同类型的炎性细胞因子与不同亚型乳腺癌之间的因果关系。基于这项研究,为不同炎症因子和不同亚型乳腺癌的机制研究提供了潜在的方向,并提出了识别和治疗不同亚型乳腺癌的潜在遗传基础。
