基于孟德尔随机化方法分析尿酸与慢性肾脏病的因果关系

目的 基于孟德尔随机化方法探究尿酸（uric acid，UA）与慢性肾脏病（chronic kidney disease，CKD）之间的因果关系。方法 以UA与CKD形成的全基因组关联研究数据库为基础，筛选出单核苷酸多态性位点(single nucleotide polymorphisms，SNPs)，参数设为P＜5×10-8、连锁不平衡r2＜0.01、kb = 10 000，运用逆方差加权法(inverse - variance weighted，IVW)、MR - Egger回归法、加权中位数法、基于众数的简单估计和基于众数的加权估计5种互补的方法进行孟德尔随机化分析，以OR值及95%CI评价UA与CKD之间的因果关系，利用异质性检验、水平多效性、逐个剔除检验等进行敏感性分析。设UA与痛风（GOUT）之间的因果关系为阳性对照。结果 共筛选24个与UA和CKD均相关的SNPs，IVW结果显示UA与CKD之间具有相关性，但不存在因果关系，UA升高不是CKD发生的危险因素（OR = 0.95，95%CI: 0.78～1.16）。以GOUT作为阳性对照，IVW结果显示UA与GOUT之间具有显著的因果关系（OR = 1.60，95%CI: 1.22～2.10），随着UA水平的不断升高GOUT的患病率逐渐增加。敏感性分析表明MR结果具有稳健性。结论 UA与CKD之间有相关性，但未有充分的证据表明UA与CKD之间存在因果关系，故单纯降低UA不能减少CKD的发生风险。

The causal relationship between uric acid and chronic kidney disease based on Mendelian randomization method

Objective To investigate the causal relationship between uric acid (UA) and chronic kidney disease (CKD) based on Mendelian randomization method. Methods Based on the genome-wide association research database of UA and CKD, single nucleotide polymorphisms (SNPs) were selected with P<5×10-8, linkage disequilibrium (LD) r2 <0.01, and kb =10 000. The Mendelian randomization analysis was carried out by using five complementary methods including inverse variance weighted(IVW), MR-Egger regression, weighted median method, simple estimator based on mode, and weighted estimator based on mode. Odds ratio(OR) value and 95% confidence interval(95%CI) were used to evaluate the causal relationship between UA and CKD, and sensitivity analysis was performed using heterogeneity test, horizontal pleiotropic test, and one by one elimination test. The causal relationship between UA and GOUT was set as a positive control. Results A total of 24 SNPs associated with UA and CKD were selected. IVW results showed a correlation between UA and CKD, but there was no causal relationship. Increased UA was not a risk factor for the occurrence of CKD (OR=0.95, 95%CI: 0.78-1.16). Using gout as the positive control, IVW results showed a significant causal relationship between UA and GOUT (OR=1.60, 95%CI: 1.22-2.10), and the prevalence of GOUT gradually increased with the increase of UA level. Sensitivity analysis showed that MR results were robust. Conclusion There is a correlation between UA and CKD, but there is no sufficient evidence of a causal relationship between UA and CKD. Therefore, reducing UA alone cannot reduce the risk of CKD.