Association of Lipid-lowering Drugs With Osteoarthritis Outcomes From a Drug-target Mendelian Randomization Study
Weiwei Ma, Honggu Chen, Zhiwen Zhang, Yong Xiong
Abstract
Background
Osteoarthritis (OA), a prevalent musculoskeletal disorder, has been suggested to have a potential association with metabolic syndrome, particularly lipid metabolism. Studies exploring the effects of lipid-lowering drugs on OA have yielded conflicting results.
Objective
This study employed a drug-targeted Mendelian randomization approach to investigate the association between genetically predicted lipid-modulating effects of commonly targeted lipid-lowering agents and the risk of OA, with the aim of providing a theoretical foundation for the use of lipid-lowering drugs in OA treatment.
Introduction
Osteoarthritis (OA) is a complex joint disorder with multifactorial etiology, characterized by the manifestation of joint pain, restricted joint mobility, and the potential for functional impairment. The pathogenesis of OA is characterized by synovitis, cartilage damage, excessive bone formation, and subchondral bone remodeling, often affecting multiple joints including the hand, hip, and knee [1, 2]. Presently, approximately 25% of the global population is afflicted with OA, with knee osteoarthritis (KOA) being the most prevalent form [3]. OA predominantly affects middle-aged and elderly women, and its etiology remains elusive, leading to a lack of effective treatments. In recent years, numerous investigations have suggested a potential association between the development of OA and metabolic syndrome (MetS), particularly involving lipid metabolism [4, 5]. With the shift in dietary patterns, hyperlipidemia has emerged as a significant health hazard among middle-aged and elderly individuals, contributing to cardiovascular disorders such as coronary heart disease, atherosclerosis, and hypertension. Growing evidence indicates the presence of abnormal lipid metabolism in OA patients, indicating that hyperlipidemia may serve as a risk factor for OA [6–8]. Lipid-lowering agents are established therapeutic interventions for hyperlipidemia, and multiple studies have demonstrated their antioxidant, antiproliferative, and anti-inflammatory properties, in addition to their lipid-lowering effects.
Materials and methods
All the studies incorporated in our analysis had received approval from their respective academic ethics review committees, and every participant had provided written informed consent. Ethical approval and consent to participate in the original GWASs were acquired from the appropriate review boards. It’s important to note that this current study constitutes a re-analysis of publicly accessible GWAS data, and therefore, no supplementary ethical approval was necessitated.
2.1 Experimental design
In the present investigation, Mendelian randomization (MR) analysis was employed to examine the potential causal relationship between lipid-lowering drugs and OA. Specifically, drug-target MR analysis was conducted to explore the association between genetically proxied inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR, statin targets), Niemann-Pick C1-Like 1 (NPC1L1, ezetimibe target), proprotein convertase subtilisin/kexin type 9 (PCSK9, evolocumab and alirocumab targets), cholesterylester transfer protein (CETP, anacetrapib target), low-density lipoprotein receptor (LDLR), and apolipoprotein B (APOB, mipomersen target), and the risk of OA.
Result
3.1 Genetic instruments selection
We procured an array of genetic variants associated with LDL cholesterol levels from the GWAS summary data collated by the Global Lipids Genetics Consortium. From the dataset, we extracted 7, 12, 3, 9, 8, and 9 SNPs associated with the HMGCR, PCSK9, NPC1L1, APOB, CETP, and LDLR genes, respectively. These SNPs were selected based on rigorous criteria to ensure the robustness of our instrumental variables. Further details are provided in S1 Table in S1 Data. Our study, with F-statistics exceeding 10 for all instrumental variants, illustrates a successful mitigation of bias that could result from weak instrumental variables. Using LDL cholesterol GWAS-proposed instruments (S2 Table in S1 Data) for our positive control study, we identified significant associations between drug exposure and coronary heart disease prevalence, affirming the efficacy of the genetic instruments we selected.
Discussion
To our current knowledge, this study represents the inaugural endeavor to investigate the causal association between drug target-mediated lipid levels and OA, encompassing both knee and hip arthritis. We employed a Mendelian randomization approach to ensure the reliability of our findings by leveraging genetic variants to control for potential confounding factors. A two-sample Mendelian randomization study was conducted utilizing publicly available GWAS datasets. The results presented in Fig 2 and S3 Table in S1 Data indicate a suggested correlation between lipid-lowering drugs and OA. Furthermore, our robustness analysis demonstrated the consistency and stability of our results.
Acknowledgments
The authors would like to acknowledge the eQTLGen, GEFOS and UK Biobank consortiums for providing original data for our Mendelian randomization analyses.
Citation: Ma W, Chen H, Zhang Z, Xiong Y (2024) Association of lipid-lowering drugs with osteoarthritis outcomes from a drug-target Mendelian randomization study. PLoS ONE 19(2): e0293960. https://doi.org/10.1371/journal.pone.0293960
Editor: Luiz Sérgio Fernandes de Carvalho, Catholic University of Brasilia, BRAZIL
Received: July 13, 2023; Accepted: October 23, 2023; Published: February 28, 2024
Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The datasets analyzed in this study are publicly available summary statistics. Summary statistics for the GWASs concerning the exposures and outcome are available from the IEU GWAS database (https://gwas.mrcieu.ac.uk/).
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0293960#abstract0
