同型半胱氨酸与估计肾小球滤过率和慢性肾病的因果关系研究

A study on the causal relationship of homocysteine to estimated glomerular filtration rate and chronic kidney disease

目的:传统的流行病学研究表明,同型半胱氨酸与估计肾小球滤过率(eGFR)和慢性肾病(CKD)之间存在相关性,但尚不清楚这种关联是否是因果关联。因此,本研究的目的是探讨同型半胱氨酸与eGFR和CKD之间的因果关联。方法:以与同型半胱氨酸显著相关的18个单核苷酸多态性(SNPs)作为工具变量,本研究使用来自全基因组关联研究的汇总数据(eGFR和CKD,n=567,460)进行了两样本的孟德尔随机化(MR)分析和敏感性分析。结果:逆方差加权、MR Egger回归和加权中位数方法都显示同型半胱氨酸与eGFR和CKD无因果关联(均P>0.05)。Cochrane’s Q检验提示与同型半胱氨酸显著相关的11个SNPs之间可能存在异质性。MR Egger回归表明不存在水平多效性。Leave-one-out法表明,没有单一的SNP驱动MR分析结果。结论:同型半胱氨酸与eGFR和CKD之间不存在因果关联,即同型半胱氨酸并不直接导致eGFR降低或CKD的发生。因此,同型半胱氨酸水平不太可能是eGFR降低和/或CKD的预测风险指标或临床重要目标。

Background:Traditional epidemiological studies have shown that homocysteine is related to estimated glomerular filtration rate(eGFR)and chronic kidney disease(CKD),but it is not clear whether there is causal relationship of homocysteine to eGFR or CKD.Therefore,the purpose of this study is to explore the causal relationship of homocysteine to eGFR and CKD.Methods:Using 18 single nucleotide polymorphisms(SNPs)significantly associated with homocysteine as instrumental variables,this study performed two-sample Mendelian randomization(MR)analyses and sensitivity analyses using summary data from genome-wide association study(n=567,460 for eGFR and CKD).Results:The results of inverse variance weighted,MR-Egger regression and weighted median analyses all showed that there was no causal effects of homocysteine on eGFR and CKD(All P>0.05).Cochrane’s Q test suggested the possibility of heterogeneity among the 11 SNPs significantly correlated with homocysteine.The MR-Egger regression showed that there was no directional pleiotropy.The leave-one-out analysis showed that the MR analysis results were not driven by a single SNP.Conclusion:There is no causal relationship of homocysteine to eGFR or CKD,that is,homocysteine does not directly cause eGFR reduction or CKD.Therefore,it is unlikely for homocysteine levels to be a predictive risk marker or clinically important target for eGFR reduction and/or CKD in the future.