Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study

作者全名：Shao, Fengling; Yao, Yingling; Weng, Dunchu; Wang, Runzhi; Liu, Ruiling; Zhang, Yongjia; Li, Erhan; Wang, Mengdi; Tang, Yuewu; Ding, Yubin; Xie, Yajun

作者地址：[Shao, Fengling; Weng, Dunchu; Wang, Runzhi; Xie, Yajun] Chongqing Med Univ, Minist Educ, Coll Lab Med, Key Lab Lab Med Diagnost, Chongqing, Peoples R China; [Yao, Yingling; Liu, Ruiling; Zhang, Yongjia; Li, Erhan; Wang, Mengdi; Ding, Yubin] Chongqing Med Univ, Women & Childrens Hosp, Dept Obstet & Gynecol, Chongqing, Peoples R China; [Yao, Yingling; Liu, Ruiling; Zhang, Yongjia; Li, Erhan; Wang, Mengdi; Ding, Yubin] Chongqing Med Univ, Minist Educ China, Sch Publ Hlth, Joint Int Res Lab Reprod & Dev, Chongqing, Peoples R China; [Yao, Yingling; Liu, Ruiling; Zhang, Yongjia; Li, Erhan; Wang, Mengdi; Ding, Yubin] Changsha Med Univ, Dept Pharmacol, Academician Workstat, Changsha, Peoples R China; [Tang, Yuewu] Chongqing Univ, Chongqing Gorges Cent Hosp 3, Gorges Hosp 3, Dept Nephrol, Chongqing, Peoples R China

通信作者：Xie, YJ (通讯作者)，Chongqing Med Univ, Minist Educ, Coll Lab Med, Key Lab Lab Med Diagnost, Chongqing, Peoples R China.; Ding, YB (通讯作者)，Chongqing Med Univ, Women & Childrens Hosp, Dept Obstet & Gynecol, Chongqing, Peoples R China.; Ding, YB (通讯作者)，Chongqing Med Univ, Minist Educ China, Sch Publ Hlth, Joint Int Res Lab Reprod & Dev, Chongqing, Peoples R China.; Ding, YB (通讯作者)，Changsha Med Univ, Dept Pharmacol, Academician Workstat, Changsha, Peoples R China.; Tang, YW (通讯作者)，Chongqing Univ, Chongqing Gorges Cent Hosp 3, Gorges Hosp 3, Dept Nephrol, Chongqing, Peoples R China.

来源：FRONTIERS IN NUTRITION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001224755000001

JCR分区：Q2

影响因子：4

年份：2024

卷号：11

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：plasma circulating metabolites; nephritis; two-sample Mendelian randomization; therapeutic agents; bioinformatics

摘要：Background: Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships. Methods: Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables' (IVs) assumptions. Results: Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], p = 0.004). Reduced alpha-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy. Conclusion: Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.

基金机构：National Natural Science Foundation of China10.13039/501100001809 [GSE72326]

基金资助正文：We thank all those who contributed to the GWAS study cohort in Table 1, and those who contributed to the two transcriptomics cohorts GSE115857 and GSE72326.