TY - JOUR
T1 - Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis
AU - Fu, Kai
AU - Si, Shucheng
AU - Jin, Xinzhong
AU - Zhang, Yan
AU - Duong, Vicky
AU - Cai, Qianying
AU - Li, Guangyi
AU - Oo, Win Min
AU - Zheng, Xianyou
AU - Boer, Cindy G.
AU - Zhang, Yuqing
AU - Wei, Xiaojuan
AU - Zhang, Changqing
AU - Gao, Youshui
AU - Hunter, David J.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/9
Y1 - 2024/9
N2 - Background: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. Methods: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. Findings: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50–2.84, P < 3 × 10−4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48–0.76, P < 3 × 10−4), finger (OR: 0.50, 95% CI: 0.35–0.73, P < 3 × 10−4), and thumb (OR: 0.49, 95% CI: 0.34–0.71, P < 3 × 10−4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype. Interpretation: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs.
AB - Background: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. Methods: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. Findings: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50–2.84, P < 3 × 10−4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48–0.76, P < 3 × 10−4), finger (OR: 0.50, 95% CI: 0.35–0.73, P < 3 × 10−4), and thumb (OR: 0.49, 95% CI: 0.34–0.71, P < 3 × 10−4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype. Interpretation: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs.
UR - http://www.scopus.com/inward/record.url?scp=85201279407&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2024.105285
DO - 10.1016/j.ebiom.2024.105285
M3 - Article
C2 - 39153411
AN - SCOPUS:85201279407
SN - 2352-3964
VL - 107
JO - EBioMedicine
JF - EBioMedicine
M1 - 105285
ER -