Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study
ObjectiveGout is a common inflammatory arthritis and lipid metabolism plays a crucial role in urate and gout. Potential associations between urate and gout and lipid-lowering drugs have been revealed in observational studies. However, the effects of lipid-lowering drugs on urate and gout remain cont...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1398023/full |
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| author | Min Liu Na Yin Yuhang Zhu Aili Du Chunyuan Cai Pengyuan Leng |
| author_facet | Min Liu Na Yin Yuhang Zhu Aili Du Chunyuan Cai Pengyuan Leng |
| author_sort | Min Liu |
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| description | ObjectiveGout is a common inflammatory arthritis and lipid metabolism plays a crucial role in urate and gout. Potential associations between urate and gout and lipid-lowering drugs have been revealed in observational studies. However, the effects of lipid-lowering drugs on urate and gout remain controversial. The aim of this study was to investigate the genetic association between lipid-lowering drugs and urate and gout.MethodsIn this study, two genetic proxies were employed to approximate lipid-lowering drug exposure: expression quantitative trait loci (eQTL) associated with drug-target genes and genetic variations proximal to or within genes targeted by these drugs, which are linked to low-density lipoprotein cholesterol (LDL-C) levels. The study’s exposures encompassed genetic variants within drug target genes (HMGCR, PCSK9, NPC1L1), each representing distinct lipid-lowering mechanisms. Causal effects were estimated using the inverse variance weighting (IVW) method, while the Summary Data-based Mendelian Randomization (SMR) method, leveraging pooled data, was applied to compute effect estimates. These estimates were further refined through various approaches including MR-Egger, the weighted median method, simple and weighted models, and leave-one-out analyses to conduct sensitivity analyses.ResultThe analytical outcomes utilizing the IVW method indicated that inhibitors of HMGCR were correlated with an elevated risk of developing gout (IVW: OR [95%CI] = 1.25 [1.03, 1.46], p=0.0436), while PCSK9 inhibitors were linked to heightened levels of urate (IVW: OR [95%CI] = 1.06 [1.01,1.10], p=0.0167). Conversely, no significant correlation between NPC1L1 inhibitors and the levels of urate or the risk of gout was established. Furthermore, the SMR analysis failed to identify significant associations between the expression levels of the HMGCR, PCSK9, and NPC1L1 genes and the risk of gout or elevated urate levels (SMR method: all P values >0.05). Sensitivity analyses further confirmed the robustness of these results, with no significant heterogeneity or pleiotropy found.ConclusionThis study furnishes novel causal evidence supporting the potential genetic correlation between the use of lipid-lowering drugs and the incidence of gout as well as urate levels. The findings indicate that inhibitors targeting HMGCR may elevate the risk associated with the development of gout, while inhibitors targeting PCSK9 are likely to increase urate concentrations. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-53cc6abbf34941339f72766d9f429bd42025-01-24T05:21:23ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-01-011510.3389/fendo.2024.13980231398023Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization studyMin Liu0Na Yin1Yuhang Zhu2Aili Du3Chunyuan Cai4Pengyuan Leng5Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaCollege of Nursing, Hangzhou Normal University, Hangzhou, ChinaDepartment of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaObjectiveGout is a common inflammatory arthritis and lipid metabolism plays a crucial role in urate and gout. Potential associations between urate and gout and lipid-lowering drugs have been revealed in observational studies. However, the effects of lipid-lowering drugs on urate and gout remain controversial. The aim of this study was to investigate the genetic association between lipid-lowering drugs and urate and gout.MethodsIn this study, two genetic proxies were employed to approximate lipid-lowering drug exposure: expression quantitative trait loci (eQTL) associated with drug-target genes and genetic variations proximal to or within genes targeted by these drugs, which are linked to low-density lipoprotein cholesterol (LDL-C) levels. The study’s exposures encompassed genetic variants within drug target genes (HMGCR, PCSK9, NPC1L1), each representing distinct lipid-lowering mechanisms. Causal effects were estimated using the inverse variance weighting (IVW) method, while the Summary Data-based Mendelian Randomization (SMR) method, leveraging pooled data, was applied to compute effect estimates. These estimates were further refined through various approaches including MR-Egger, the weighted median method, simple and weighted models, and leave-one-out analyses to conduct sensitivity analyses.ResultThe analytical outcomes utilizing the IVW method indicated that inhibitors of HMGCR were correlated with an elevated risk of developing gout (IVW: OR [95%CI] = 1.25 [1.03, 1.46], p=0.0436), while PCSK9 inhibitors were linked to heightened levels of urate (IVW: OR [95%CI] = 1.06 [1.01,1.10], p=0.0167). Conversely, no significant correlation between NPC1L1 inhibitors and the levels of urate or the risk of gout was established. Furthermore, the SMR analysis failed to identify significant associations between the expression levels of the HMGCR, PCSK9, and NPC1L1 genes and the risk of gout or elevated urate levels (SMR method: all P values >0.05). Sensitivity analyses further confirmed the robustness of these results, with no significant heterogeneity or pleiotropy found.ConclusionThis study furnishes novel causal evidence supporting the potential genetic correlation between the use of lipid-lowering drugs and the incidence of gout as well as urate levels. The findings indicate that inhibitors targeting HMGCR may elevate the risk associated with the development of gout, while inhibitors targeting PCSK9 are likely to increase urate concentrations.https://www.frontiersin.org/articles/10.3389/fendo.2024.1398023/fulldrug targetseQTLgoutlipid-lowering drugsMendelian randomizationurate |
| spellingShingle | Min Liu Na Yin Yuhang Zhu Aili Du Chunyuan Cai Pengyuan Leng Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study Frontiers in Endocrinology drug targets eQTL gout lipid-lowering drugs Mendelian randomization urate |
| title | Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study |
| title_full | Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study |
| title_fullStr | Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study |
| title_full_unstemmed | Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study |
| title_short | Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study |
| title_sort | associations between lipid lowering drugs and urate and gout outcomes a mendelian randomization study |
| topic | drug targets eQTL gout lipid-lowering drugs Mendelian randomization urate |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1398023/full |
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