ABSTRACT
INTRODUCTION: Research has highlighted the role of runt-related transcription factor 2 (Runx2) in the development of osteoarthritis (OA); however, its causal association remains unclear. This study aimed to explore whether Runx2 expression is causally associated with OA and assess its therapeutic potential for OA. METHODS: Genetic proxy instruments for Runx2 expression were obtained from gene expression quantitative trait locus (eQTLs) study of eQTLGen Consortium (n = 31,684). Aggregated genome-wide association study (GWAS) data for OA (including all OA [177,517 cases and 649,173 controls], knee OA (KOA) [62,497 cases and 333,557 controls], and hip OA (HOA) [36,445 cases and 316,943 controls]) were extracted from the Genetics of Osteoarthritis Consortium. We integrated eQTLs data with OA GWAS data to estimate their causal association and to estimate the potential of Runx2 as a drug target in the treatment of OA using summary data-based Mendelian randomization (SMR) analysis. Furthermore, different OA GWAS data (including all OA [77,052 cases and 378,169 controls], KOA [24,955 cases and 378,169 controls], and HOA [15,704 cases and 378,169 controls]) derived from the GWAS Catalog database were used for replication study. RESULTS: SMR analysis showed that high expression levels of Runx2 were associated with an increased risk of all OA [odds ratio (OR) 1.044, 95% confidence interval (CI) 1.023-1.067; P = 5.03 × 10-5], KOA (OR 1.040, 95% CI 1.006-1.075; P = 0.021), and HOA (OR 1.067, 95% CI 1.022-1.113; P = 0.003). This suggests that Runx2 inhibitors may have promising potential for the treatment of OA. Notably, the causal effects of Runx2 with all OA (OR 1.053, 95% CI 1.027-1.079; P = 3.95 × 10-5) and KOA (OR 1.043, 95% CI 1.001-1.087; P = 0.045) were repeated in the replication study, but limited evidence supported the association of Runx2 expression levels with HOA (OR 1.045, 95% CI 0.993-1.101; P = 0.094). CONCLUSIONS: Our analyses indicate a positive correlation between Runx2 expression and OA risk across all three phenotypes, suggesting the potential of Runx2 inhibitors in the treatment of OA and providing evidence from a genetic perspective.
ABSTRACT
BACKGROUND: Previous traditional observational studies have suggested the contribution of several cytokines and growth factors to the development of osteoarthritis (OA). This study aimed to determine the association of circulating cytokine and growth factor levels with OA. METHODS: We used two-sample Mendelian randomization (MR) to explore the causality between circulating cytokine and growth factor levels and OA [including knee or hip OA (K/HOA), knee OA (KOA), and hip OA (HOA)]. Summary level data for circulating cytokine and growth factor levels were sourced from a genome-wide association study (GWAS) involving 8,293 participants of Finnish ancestry. Single-nucleotide polymorphisms related to K/HOA (39,427 cases and 378,169 controls), KOA (24,955 cases and 378,169 controls), and HOA (15,704 cases and 378,169 controls) were obtained from a previous GWAS. The inverse variance weighted (IVW) method was primarily used for our MR analysis. For exposures to only one relevant SNP as IV, we used the Wald ratio as the major method to assess causal effects. We also conducted a series of sensitivity analyses to improve the robustness of the results. RESULTS: Circulating vascular endothelial growth factor levels were suggestively associated with an increased risk of K/HOA (odds ratio (OR) = 1.034; 95 % confidence interval (CI) = 1.013-1.055; P = 0.001), KOA (OR = 1.034; 95 % CI = 1.014-1.065; P = 0.002), and HOA (OR = 1.039; 95 % CI = 1.003-1.067; P = 0.034). Circulating interleukin (IL)-12p70 levels was suggestively associated with K/HOA (OR = 1.047; 95 % CI = 1.018-1.077; P = 0.001), KOA (OR = 1.058; 95 % CI = 1.022-1.095; P = 0.001), and HOA (OR = 1.044; 95 % CI = 1.000-1.091; P = 0.048). Circulating IL-18 levels were suggestively associated with HOA (OR = 1.068; 95 % CI = 1.014-1.125; P = 0.012). However, limited evidence exists to support causal genetic relationships between other circulating cytokines, growth factor levels and K/HOA, KOA, and HOA. CONCLUSIONS: Our MR analysis provides suggestive evidence of causal relationships between circulating cytokines and growth factors levels and OA, providing new insights into the etiology of OA.
