高血压与恶性肿瘤的因果关系:一项孟德尔随机化研究

Causality between hypertension and malignant tumors:A Mendelian randomization study

目的评估14种恶性肿瘤与高血压之间的因果关系。方法使用全基因组关联研究的公开数据集,从中提取与高血压、14种恶性肿瘤强相关的独立遗传变异作为工具变量进行双向孟德尔随机化(Mendelian randomization,MR)分析,包括随机效应逆方差加权(inverse variance weighted,IVW)、简单模式、加权中位数、加权模式和MR-Egger评估因果效应,通过敏感度分析检验分析结果的有效性和稳健性,并通过多变量MR分析进一步控制混杂因素的影响。结果在恶性黑色素瘤与高血压的MR分析中,共纳入11个与恶性黑色素瘤强相关的单核苷酸多态性(single nucleotide polymorphism,SNP),经Bonferroni校正,基于IVW的结果显示,恶性黑色素瘤与高血压的发生具有因果关系(OR=1.67,95%CI:1.27~2.21,P<0.001)。经Cochran’s Q检验、孟德尔随机多效性残差和异常值检验及MR-Egger截距测试显示工具变量之间均不存在离群值及水平多效性,留一法敏感度分析显示不存在对整体结果有较大影响单个SNP。高血压与白血病的初步分析结果显示二者可能存在关系,但在逐次调整混杂因素后高血压对白血病发生风险的影响不再具有显著性。结论恶性黑色素瘤可能是发生高血压的危险因素。

Objective To assess the causality between 14 malignant tumors and hypertension.Methods Publicly available datasets from genome-wide association study were used,from which independent genetic variants strongly associated with hypertension and 14 malignant tumors were extracted as instrumental variables for bidirectional Mendelian randomization(MR)analysis,including random effect inverse variance weighted(IVW),simple mode,weighted median,weighted mode and MR-Egger to evaluate the causal effect.Sensitivity analysis was used to test the validity and robustness of the analytical results,and multivariate MR method was used to further control for the effects of confounding factors.Results In the MR analysis of malignant melanoma and hypertension,the study included a total of 11 single nucleotide polymorphisms(SNPs)strongly associated with malignant melanoma.After Bonferroni correction,the IVW-based results showed a causal relationship between malignant melanoma and hypertension(OR=1.67,95%CI:1.27-2.21,P<0.001).Cochran’s Q test,Mendelian randomization pleiotropy residual sum and outlier test and MR-Egger intercept test showed that there were no outliers and no horizontal pleiotropy among the instrumental variables,and the sensitivity analysis of the leave-one-out method showed that there was no single SNP that had a significant impact on the overall results.In the analysis of hypertension and leukemia,the preliminary analysis results showed that there may be a relationship between the two,but after adjusting for confounders,the effect of hypertension on the risk of leukemia was no longer significant.Conclusion Malignant melanoma may be a risk factor in the development of hypertension.