Causal relationship between type 2 diabetes and renal cell carcinoma based on a two-sample Mendelian randomization study
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摘要: 目的 采用双样本孟德尔随机化探究2型糖尿病和肾癌的因果关系。方法 从GWAS Catalog数据库中筛选与2型糖尿病相关的单核苷酸多态性位点(P < 5×10-8)作为工具变量，用逆方差加权法作为主要的分析方法，并采用MR-Egger回归和加权中位数法作为补充。比值比(odd ratio，OR)值和95%置信区间(confidence interval，CI)用于评价2型糖尿病和肾癌之间是否存在因果关系。采用MR多效性检测水平多效性，采用留一法检测敏感性。结果 从UKB数据库男性和女性肾癌数据集中分别提取了152个SNP作为工具变量。MR-Egger回归、加权中位数和逆方差加权方法得到OR值和95%CI：女性1.27(95%CI：1.04~1.55)，差异有统计学意义(P=0.003 5)；男性1.04(95%CI：0.98~1.10)，差异无统计学意义(P=0.33)。mr_pleiotropy_test显示水平多效性不显著。在进行留一敏感性分析后，没有观察到任何特定SNP位点对结果的显著影响，表明结果具有高度的稳定性和可靠性。结论 双样本孟德尔随机化分析显示2型糖尿病与女性肾癌可能存在因果关联。然而，需要进一步验证更大的样本量和来自不同种族背景的个人的数据，以加强研究结果。Abstract: Objective To investigate the potential causal relationship between type 2 diabetes and renal cell carcinoma by a two-sample Mendelian randomization method.Methods Single nucleotide polymorphisms(SNPs) associated with type 2 diabetes(P < 5×10-8) were screened from the GWAS Catalog database as instrumental variables. The inverse variance weighting method was used as the main analysis method, and MR-Egger regression and weighted median method were used to supplement the explanation. Odd ratio(OR) values and 95% confidence interval(CI) were used to evaluate the causal relationship between type 2 diabetes and renal cell carcinoma. Level pleiotropy was tested by mr_pleiotropy_test, and sensitivity was tested by leave-one-out method.Results From the UKB database male and female renal cell carcinoma data sets, 152 SNPs were extracted as instrumental variables, respectively. The MR-Egger regression, weighted median, and inverse variance weighting methods were used to obtain OR value and 95% CI: female 1.27(95%CI: 1.04-1.55) with statistical significance(P=0.003 5), male 1.04(95%CI: 0.98-1.10) without statistical significance(P=0.33). Mr_pleiotropy_test showed that horizontal pleiotropy was not statistically significant. After leave-one-out sensitivity analysis was performed, no significant effect of any specific SNP locus was observed, indicating a high degree of stability and reliability of the results.Conclusion The two-sample Mendelian randomization analysis showed a possible causal association between type 2 diabetes and renal cell carcinoma in women. However, further validation with larger sample sizes and data from individuals with different ethnic backgrounds is needed to strengthen the findings.
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表 1 数据来源
数据库 数据集 描述 样本量/例 人群 包含SNP数量/个 病例来源 暴露数据集 Gwas Catalog GCST90018926 T2DM患者 490089 欧洲 24167560 根据ICD10的疾病分类招募参与者 结局数据集 UKB 20001_1034 男性肾癌患者
女性肾癌患者7119 3 780 英国 13791467 参与者的登记数据和自我报告的信息(由经验丰富的护士访谈验证) 
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表 2 女性肾癌患者中5种MR分析方法结果
方法 b SE P值 OR(95%CI) Q Q P值 IVW 0.24 0.10 0.003 5 1.27(1.04~1.55) 132.90 0.85 MR-Egger 0.42 0.03 0.037 1 1.05(1.44~1.61) 132.24 0.85 加权中位数 0.27 0.09 0.075 1 1.31(1.10~1.56) 加权模式 0.38 0.15 0.062 6 1.46(1.09~1.96) 简单模式 0.36 0.04 0.349 3 1.43(1.32~1.55)
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表 3 男性肾癌患者中5种MR分析方法结果
方法 b SE P值 OR(95%CI) IVW 0.04 0.03 0.33 1.04(0.98~1.10) MR-Egger 0.19 0.05 0.65 1.21(1.10~1.33) 加权中位数 -0.01 0.04 0.11 0.99(0.92~1.07) 加权模式 -0.06 0.19 0.18 0.94(0.65~1.37) 简单模式 -0.11 0.11 0.17 0.99(0.80~1.23)
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