Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease
ObjectiveThe 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.MethodsWe extracted 11 genetic variants encoding targets of...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1434145/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841540139775426560 |
|---|---|
| author | Yi Zhang Yi Zhang Guangyang Ou Lei Peng Jian Pan Shaohua Zhang Jianguo Shi |
| author_facet | Yi Zhang Yi Zhang Guangyang Ou Lei Peng Jian Pan Shaohua Zhang Jianguo Shi |
| author_sort | Yi Zhang |
| collection | DOAJ |
| description | ObjectiveThe 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.MethodsWe 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.ResultsThe 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).ConclusionThrough 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. |
| format | Article |
| id | doaj-art-a46c279e04d8439aba55e22ccc7a88c8 |
| institution | Kabale University |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj-art-a46c279e04d8439aba55e22ccc7a88c82025-01-14T05:10:36ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-01-011510.3389/fendo.2024.14341451434145Genetic association analysis of lipid-lowering drug target genes in chronic kidney diseaseYi Zhang0Yi Zhang1Guangyang Ou2Lei Peng3Jian Pan4Shaohua Zhang5Jianguo Shi6Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou Medical University, Jinzhou, Liaoning, ChinaDepartment of Urology, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou Medical University, Jinzhou, Liaoning, ChinaDepartment of Cardiology, Hunan University of Chinese Medicine, Changsha, ChinaMotor Robotics Institute (MRI), South China Hospital, Health Science Center, Shenzhen University, Shenzhen, ChinaMotor Robotics Institute (MRI), South China Hospital, Health Science Center, Shenzhen University, Shenzhen, ChinaMotor Robotics Institute (MRI), South China Hospital, Health Science Center, Shenzhen University, Shenzhen, ChinaDepartment of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou Medical University, Jinzhou, Liaoning, ChinaObjectiveThe 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.MethodsWe 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.ResultsThe 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).ConclusionThrough 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.https://www.frontiersin.org/articles/10.3389/fendo.2024.1434145/fullchronic kidney diseaselipid-lowering druglipidsMendelian randomization analysisestimated glomerular filtration rate |
| spellingShingle | Yi Zhang Yi Zhang Guangyang Ou Lei Peng Jian Pan Shaohua Zhang Jianguo Shi Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease Frontiers in Endocrinology chronic kidney disease lipid-lowering drug lipids Mendelian randomization analysis estimated glomerular filtration rate |
| title | Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease |
| title_full | Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease |
| title_fullStr | Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease |
| title_full_unstemmed | Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease |
| title_short | Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease |
| title_sort | genetic association analysis of lipid lowering drug target genes in chronic kidney disease |
| topic | chronic kidney disease lipid-lowering drug lipids Mendelian randomization analysis estimated glomerular filtration rate |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1434145/full |
| work_keys_str_mv | AT yizhang geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease AT yizhang geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease AT guangyangou geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease AT leipeng geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease AT jianpan geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease AT shaohuazhang geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease AT jianguoshi geneticassociationanalysisoflipidloweringdrugtargetgenesinchronickidneydisease |