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Published on: March 18, 2022
Metalloproteins as risk factors for osteoarthritis: improving and understanding causal estimates using Mendelian
Jiaze Li1, Mingyang Guan1, Lin Qi1
1Department of Orthopedics, Dalian Third People's Hospital Affiliated to Dalian Medical University, Dalian City Third People's Hospital, Dalian, 116091, Liaoning Province, China.
Abstract:
Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorders and a primary cause of pain and disability among the elderly population. Research on the relationship between metalloproteins (MPs) and OA is limited, and causality remains unclear. Our objective is to utilize Mendelian randomization (MR) to explore the possible causal relationship between MPs and OA. The data on MPs were derived from a Genome-Wide Association Study (GWAS) analysis involving 3301 samples. The GWAS data for OA were obtained from an analysis involving 462,933 European individuals. In this study, a variety of two-sample Mendelian randomization methods (two-sample MR) to evaluate the causal effect of MPs on OA, including inverse variance weighted method (IVW), MR-Egger method, weighted median method (WM), simple mode, weight mode, and Wald ratio. The primary MR analysis using the IVW method reveals a significant negative correlation between Metallothionein-1F (MT-1F), zinc finger protein 134 (ZNF134), calcium/calmodulin-dependent protein kinase type 1D (CAMK1D), and EF-hand calcium-binding domain-containing protein 14 (EFCAB14) with the occurrence of osteoarthritis (OA) (p value < 0.05). However, no causal relationship was observed in the opposite direction between these MPs and OA. Notably, even in combined models accounting for confounding factors, the negative association between these four MPs and OA remained significant. Sensitivity analysis demonstrated no evidence of horizontal pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the results. In this study, we have established a conspicuous association between four distinct MPs and OA. This discovery augments our understanding of potential avenues for the diagnosis and treatment of this condition. Key Points • The MR method was employed to assess the relationship between MPs and OA. • A total of four types of MPs have demonstrated inhibitory effects on the occurrence of OA.
Insights
Mendelian randomization revealed four metalloproteins (MPs) may protect against osteoarthritis (OA). This study suggests specific MPs could offer new diagnostic and therapeutic targets for this common joint disease.
Area of Science:
- Genetics and Molecular Biology
- Rheumatology and Musculoskeletal Disorders
Background:
- Osteoarthritis (OA) is a leading cause of disability in the elderly, yet the role of metalloproteins (MPs) in its development is not well understood.
- Limited research exists on the causal relationship between MPs and OA, highlighting a gap in current knowledge.
Purpose of the Study:
- To investigate the potential causal relationship between various metalloproteins (MPs) and the incidence of osteoarthritis (OA) using Mendelian randomization (MR).
- To identify specific MPs that may influence OA risk, potentially uncovering novel therapeutic targets.
Main Methods:
- Employed two-sample Mendelian randomization (MR) analysis, utilizing Genome-Wide Association Study (GWAS) data for MPs (n=3301) and OA (n=462,933).
- Applied multiple MR methods including Inverse Variance Weighted (IVW), MR-Egger, and Weighted Median to assess causality.
- Conducted sensitivity analyses (pleiotropy, heterogeneity, leave-one-out) to ensure result robustness.
Main Results:
- Significant negative causal associations were found between four specific MPs—Metallothionein-1F (MT-1F), zinc finger protein 134 (ZNF134), calcium/calmodulin-dependent protein kinase type 1D (CAMK1D), and EF-hand calcium-binding domain-containing protein 14 (EFCAB14)—and osteoarthritis (OA) (p < 0.05).
- No evidence of a causal effect of OA on these MPs was observed.
- Results remained significant after adjusting for confounding factors, and sensitivity analyses confirmed no significant horizontal pleiotropy or heterogeneity.
Conclusions:
- Four distinct metalloproteins (MT-1F, ZNF134, CAMK1D, EFCAB14) show a protective effect against osteoarthritis.
- These findings suggest a potential role for these MPs in the pathogenesis of OA and may inform future diagnostic and therapeutic strategies for the condition.
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