孟德尔随机化分析低级别浆液性卵巢癌与乳腺癌的因果关系

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doi:10.6040/j.issn.1671-7554.0.2024.0935

摘要： 目的探索低级别浆液性卵巢癌(low grade serous ovarian cancer, LGSOC)与乳腺癌(breast cancer, BC)的因果关系。方法采用双向两样本孟德尔随机化(mendelian randomization, MR)方法,使用公开的来自欧洲人群全基因组关联研究中的遗传数据,以单核苷酸多态性(single nucleotide polymorphisms, SNPs)作为工具变量,正向研究以LGSOC作为暴露变量、BC作为结局,反向研究以BC作为暴露变量、LGSOC为结局。另外对4种分子亚型BC进行亚组分析。运用逆方差加权(inverse variance weighted, IVW)、MR-Egger回归法、加权中位数、加权模型、简单模型来研究LGSOC和BC之间的因果关系。Cochrans Q检验工具变量的异质性。MR-Egger截距法检验水平多效性。结果正向研究纳入19个SNPs,MR分析结果显示,LGSOC与BC的风险增加存在正向因果关系(IVW:OR=1.05,95%CI:1.01~1.08, P=0.01)。亚组分析结果显示,LGSOC与雌激素受体(estrogen receptor, ER)阳性BC存在因果关系(P=0.07)。反向研究纳入95个SNPs,MR分析结果显示,BC与LGSOC的风险增加不存在因果关系(P>0.05)。异质性检验和多效性检验均未发现存在显著异质性和水平多效性(P>0.05)。结论欧洲人中LGSOC与BC的风险增加有正向因果关系,可能增加ER+ BC的发生风险,不支持BC与LGSOC风险增加的因果关系。

关键词: 低级别浆液性卵巢癌, 乳腺癌, 分子亚型, 孟德尔随机化, 因果关系

Abstract: Objective To explore the causal relationship between low grade serous ovarian cancer(LGSOC)and breast cancer(BC). Methods The study employed a bidirectional two sample Mendelian randomization(MR)method, and utilized publicly available genetic data from genome-wide association studies in European populations, with single nucleotide polymorphisms(SNPs)as instrumental variables. The forward study used LGSOC as the exposure variable and BC as the outcome, while the reverse study used BC as the exposure variable and LGSOC as the outcome. In addition, subgroup analysis was conducted on four molecular subtypes of BC. Inverse variance weighted(IVW), MR Egger regression, weighted median, weighted model, and simple model were used to study the causal relationship between LGSOC and BC. The Cochrans Q test was used for heterogeneity of instrumental variables. The MR Egger intercept method was used to test horizontal pleiotropy. Results The positive study included 19 SNPs, and MR analysis showed a positive causal relationship between LGSOC and increased risk of BC(IVW: OR=1.05, 95%CI: 1.01-1.08, P=0.01). Subgroup analysis showed that LGSOC may have a causal relationship with estrogen receptor positive(ER+)BC(P=0.07). The reverse study included 95 SNPs, and the MR analysis results showed that there was no causal relationship between BC and increased risk of LGSOC(P>0.05). No significant heterogeneity or horizontal pleiotropy was found in both heterogeneity and pleiotropy tests(P>0.05). Conclusion There is a positive causal relationship between LGSOC and increased risk of BC in Europeans, which may increase the risk of ER+BC. The causal relationship between BC and increased risk of LGSOC is not supported.

Key words: Low grade serous ovarian cancer, Breast cancer, Molecular subtype, Mendelian randomization, Causal relationship

中图分类号:

R737

袁宗怀,潘广晔,迟曰梅,安传国,张永刚. 孟德尔随机化分析低级别浆液性卵巢癌与乳腺癌的因果关系[J]. 山东大学学报 (医学版), 2025, 63(1): 99-107.

YUAN Zonghuai, PAN Guangye, CHI Yuemei, AN Chuanguo, ZHANG Yonggang. Causal relationship between low grade serous ovarian cancer and breast cancer analyzed by Mendelian randomization[J]. Journal of Shandong University (Health Sciences), 2025, 63(1): 99-107.

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