摘要
Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dyslipidemia,particularly secondary hyperlipemia,in patients with diabetic kidney disease.Methods We conducted a two-sample Mendelian randomization study using genome-wide association study(GWAS)summary data.Genetic variants associated with MR levels were selected as exposures,with TIN and lipid profiles[including low-density lipoprotein cholesterol(LDL-C),triglyceride,and high-density lipoprotein cholesterol]as outcomes.A two-step Mendelian randomization approach was used to assess TIN as a mediator,employing inverse variance weighted regression as the primary analysis,supplemented by Mendelian randomization-Egger,weighted median,and sensitivity analyses.Results Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN(OR=0.8598,95%CI[0.7775-0.9508],P<0.001).Although no significant causal relationship was identified between MR level and secondary hyperlipemia,a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed(OR=0.9901,95%CI[0.9821-0.9983],P=0.018).Additionally,TIN exhibited causal links with secondary hyperlipemia(OR=1.0016,95%CI[1.0002-1.0029],P=0.020)and elevated LDL-C(OR=1.0111,95%CI[1.0024-1.0199],P=0.012),particularly LDL-C in European males(OR=1.0230,95%CI[1.0103-1.0358],P<0.001).Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride(OR=0.7027,95%CI[0.6189-0.7978],P<0.001),high-density lipoprotein cholesterol(OR=1.1247,95%CI[1.0019-1.2626],P=0.046),and LDL-C(OR=0.8423,95%CI[0.7220-0.9827],P=0.029).Notably,TIN mediated 16.7%of the causal association between MR and LDL-C levels.Conclusions MR plays a critical role in the development of TIN and lipid metabolism,highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.
目的探究胞质盐皮质激素受体(mineralocorticoid receptor,MR)水平与肾小管间质性肾炎(tubulointer‐stitial nephritis,TIN)发展之间的因果关系,并评估MR对糖尿病肾病患者血脂异常,特别是继发性高脂血症的影响。方法我们利用全基因组关联研究(genome-wide association study,GWAS)汇总数据,采用双样本孟德尔随机化分析方法,以MR水平相关的遗传变异为工具变量,探讨MR对TIN及血脂等结局变量的因果效应。血脂指标包括低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、甘油三酯和高密度脂蛋白胆固醇。采用两步孟德尔随机化分析评估TIN在MR和血脂代谢之间的中介效应。孟德尔随机化分析主要采用逆方差加权法,以敏感性分析、孟德尔随机化-Egger分析和加权中位数法作为补充。结果胞质非活化MR水平与TIN风险降低呈显著因果关联(OR=0.8598,95%CI[0.7775~0.9508],P<0.001)。尽管我们未发现MR水平与继发性高脂血症呈显著因果关系,但胞质非活化MR水平可能与LDL-C水平降低存在潜在关联(OR=0.9901,95%CI[0.9821~0.9983],P=0.018)。此外,TIN与继发性高脂血症(OR=1.0016,95%CI[1.0002~1.0029],P=0.020)以及LDL-C水平升高(OR=1.0111,95%CI[1.0024~1.0199],P=0.012)均存在因果关联,TIN与LDL-C的关联在欧洲男性人群中更为明显(OR=1.0230,95%CI[1.0103~1.0358],P<0.001)。反向孟德尔随机化分析显示:TIN与甘油三酯(OR=0.7027,95%CI[0.6189~0.7978],P<0.001)、高密度脂蛋白胆固醇(OR=1.1247,95%CI[1.0019~1.2626],P=0.046)以及LDL-C(OR=0.8423,95%CI[0.7220~0.9827],P=0.029)均存在显著因果关系。TIN在MR与LDL-C水平之间的因果链中起中介作用,中介效应占比达16.7%。结论MR在TIN及脂质代谢紊乱的进展中发挥重要作用。这一结果提示以非奈利酮为代表的MR拮抗剂可望缓解肾脏损伤和预防脂质代谢相关并发症。
