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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Systems Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1434145

Genetic Association Analysis of Lipid-Lowering Drug Target Genes in Chronic Kidney Disease

Provisionally accepted
Yi Zhang Yi Zhang 1Guangyang Ou Guangyang Ou 2Lei Peng Lei Peng 3Shaohua Zhang Shaohua Zhang 3Jianguo Shi Jianguo Shi 1*
  • 1 Jinzhou Medical University, Jinzhou, China
  • 2 Hunan University of Chinese Medicine, Changsha, Anhui Province, China
  • 3 Shenzhen University, Shenzhen, Guangdong Province, China

The final, formatted version of the article will be published soon.

    Objective: The impact of lipid-lowering medications on chronic kidney disease (CKD) remains a subject of debate. This Mendelian randomization (MR) study aims to elucidate the potential effects of lipid-lowering drug targets on CKD development. Methods:We extracted 11 genetic variants encoding targets of lipid-lowering drugs from published genome-wide association study (GWAS) summary statistics, encompassing LDLR, HMGCR, PCSK9, NPC1L1, APOB, ABCG5/ABCG8, LPL, APOC3, ANGPTL3, and PPARA. A Mendelian randomization analysis was conducted targeting these drug-related genes. CKD risk was designated as the primary outcome, while estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) were assessed as secondary outcomes. Additionally, mediation analysis was performed utilizing 731 immune cell phenotypes to identify potential mediators. Results: The meta-analysis revealed a significant association between ANGPTL3 inhibitors and a reduced risk of CKD (OR [95% CI] = 0.85 [0.75-0.96]). Conversely, LDLR agonists were significantly linked to an increased risk of CKD (OR [95% CI] = 1.11 [1.02-1.22]). Regarding secondary outcomes, lipid-lowering drugs did not significantly affect eGFR and BUN levels.Mediation analysis indicated that the reduction in CKD risk by ANGPTL3 inhibitors was mediated through modulation of the immune cell phenotype, specifically HLA-DR on CD14+ CD16+ monocytes (Mediated proportion: 4.69%; Mediated effect: -0.00899). Conclusion:Through drug-targeted MR analysis, we identified a causal relationship between lipid-lowering drug targets and CKD. ANGPTL3 and LDLR may represent promising candidate drug targets for CKD treatment.

    Keywords: Chronic Kidney Disease, Lipid-lowering drug, Lipids, Mendelian Randomization Analysis, Estimated glomerular filtration rate

    Received: 13 Jun 2024; Accepted: 23 Dec 2024.

    Copyright: © 2024 Zhang, Ou, Peng, Zhang and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jianguo Shi, Jinzhou Medical University, Jinzhou, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.