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两样本孟德尔随机化分析原发性硬化性胆管炎与结直肠癌发生风险的关系
DOI: 10.3969/j.issn.1001-5256.2023.03.013
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：李镇圻负责课题设计，资料分析，撰写论文；杜宁参与收集数据，图形的可视化；和红阳负责拟定写作思路，指导撰写文章，修改文章及最后定稿。
数据可用性声明：获取本研究所有数据集的GWAS ID号可直接联系相应作者。
Association between primary sclerosing cholangitis and the risk of colorectal cancer: A two-sample Mendelian randomization study
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摘要:
目的 运用两样本孟德尔随机化(TSMR)评估原发性硬化性胆管炎(PSC)与结直肠癌(CRC)之间的关联。 方法 PSC与CRC相关的单核苷酸多态性(SNP) 数据分别来自芬兰生物银行及英国生物银行，对基于全基因组关联研究(GWAS)的所有汇总数据进行二次数据分析，选择与PSC密切关联的遗传位点作为工具变量，分别以孟德尔随机化Egger回归法、中位数加权法、IVW随机效应模型、最大似然比法、线性中位数加权法、IVW radial法、IVW固定效应模型七种方法做TSMR，以OR值评价PSC和CRC风险之间的因果关系。 结果 基因预测的PSC对CRC存在正向因果关系，以IVW固定效应模型为例，遗传决定的患PSC患者发生CRC风险增加(OR=1.002 243，95%CI：1.001 319~1.003 167)。TSMR结果不存在异质性(P=0.87)，无水平多效性(P=0.95)。本次所选PSC的3个工具变量为强工具变量(F=11.86)。 结论 TSMR发现PSC具有与CRC风险相关的遗传证据。无论是否合并炎症性肠病，在PSC患者中积极进行肠镜筛查或可有利于CRC的早期发现与及时干预。 Abstract:Objective To investigate the association between primary sclerosing cholangitis (PSC) and colorectal cancer (CRC) by using two-sample Mendelian randomization (TSMR). Methods The single nucleotide polymorphism (SNP) data associated with PSC and CRC were obtained from Finland Biobank and UK Biobank, respectively. A secondary data analysis was performed for all pooled data based on genome-wide association studies to select the genetic loci closely associated with PSC as instrumental variables, and TSMR was conducted by seven methods, i.e., Egger regression in Mendelian randomization, weighted median, inverse variance weighted (IVW) random effects model, maximum likelihood, linear weighted median, IVW radial method, and IVW fixed effects model. Odds ratio (OR) value was used to evaluate the causal relationship between PSC and the risk of CRC. Results There was a positive causal relationship between gene predicted PSC and CRC, and with the IVW fixed effects model as an example, genetically determined patients with PSC could increase the risk of CRC (OR=1.002 243, 95% confidence interval: 1.001 319-1.003 167). TSMR results showed no heterogeneity (P=0.87) or horizontal pleiotropy (P=0.95). The three instrumental variables selected for PSC were strong instrumental variables (F=11.86). Conclusion TSMR shows the genetic evidence for the association between PSC and the risk of CRC. Regardless of the presence or absence of inflammatory bowel disease, active enteroscopy screening among patients with PSC may help with the early identification and timely intervention of CRC. -
图 1 研究过程的示意图
注：假设1，与暴露显著相关；假设2，与结局不相关；假设3，与混杂因素不相关。
Figure 1. Schematic design showing the study process
图 2 7种方法的孟德尔随机化结果图
注：*，不同孟德尔随机化分析方法中的金标准参考方法。
Figure 2. Two-sample mendelian randomization results plot for seven methods
图 5 更换数据集之后的TSMR部分结果图
注：*，不同孟德尔随机分析方法中的金标准参考方法。
Figure 5. TSMR partial results before changed the data set
表 1 本项TSMR研究中的GWAS数据汇总信息
Table 1. Summary of the GWAS included in this two sample mendelian randomization study
暴露/结局 数据来源 样本种族来源 样本量 SNP的个数 性别 数据公布年份 PSC 芬兰生物银行 欧洲人群 195 992 16 380 407 男女混合 2021 CRC 英国生物银行 欧洲人群 377 673 11 738 639 男女混合 2021 注：SNP，单核苷酸多态性。 
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表 2 最终工具变量的信息
Table 2. The information for final tool variables
SNP CHR POS EA OA EAF β值 SE P值 rs3094662 6 31 121 945 C A 0.243 585 0.000 829 149 0.000 325 454 0.010 999 90 rs9268127 6 32 253 559 C T 0.190 381 0.001 158 570 0.000 355 312 0.001 099 99 rs241438 6 32 797 620 T C 0.358 179 0.000 703 693 0.000 291 436 0.016 000 00 注：CHR，染色体; POS，SNP在染色体上的位置；EA，效应等位基因; OA，非效应等位基因; EAF，效应等位基因频率; β，等位基因效应值; SE，β的标准误。
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