New Insights on the Therapeutic Potential of Runt-Related Transcription Factor 2 for Osteoarthritis: Evidence from Mendelian Randomization.

IF 2.9 3区医学 Q2 RHEUMATOLOGY

Rheumatology and Therapy Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI:10.1007/s40744-024-00682-1

Jiale Xie, Xin Xu, Mingyi Yang, Hui Yu, Jinrong Hao, Dinglong Yang, Peng Xu

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引用次数: 0

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.

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Runt 相关转录因子 2 治疗骨关节炎潜力的新见解：孟德尔随机化的证据。

导言：研究强调了Runt相关转录因子2（Runx2）在骨关节炎（OA）发病中的作用，但其因果关系仍不清楚。本研究旨在探讨Runx2的表达是否与OA存在因果关系，并评估其治疗OA的潜力：Runx2表达的遗传替代工具来自eQTLGen Consortium的基因表达定量性状位点（eQTLs）研究（n = 31,684）。从骨关节炎遗传学联盟（Genetics of Osteoarthritis Consortium）提取了OA（包括所有OA[177,517例病例和649,173例对照]、膝关节OA（KOA）[62,497例病例和333,557例对照]以及髋关节OA（HOA）[36,445例病例和316,943例对照]）的全基因组关联研究（GWAS）汇总数据。我们整合了 eQTLs 数据和 OA GWAS 数据，以估算它们之间的因果关系，并利用基于汇总数据的孟德尔随机分析（SMR）估算 Runx2 作为治疗 OA 的药物靶点的潜力。此外，从GWAS目录数据库中提取的不同OA GWAS数据（包括所有OA[77,052个病例和378,169个对照]、KOA[24,955个病例和378,169个对照]以及HOA[15,704个病例和378,169个对照]）也被用于重复研究：SMR分析表明，Runx2的高表达水平与所有OA[几率比（OR）1.044，95%置信区间（CI）1.023-1.067；P = 5.03 × 10-5]、KOA（OR 1.040，95% CI 1.006-1.075；P = 0.021）和HOA（OR 1.067，95% CI 1.022-1.113；P = 0.003）风险的增加有关。这表明，Runx2抑制剂可能具有治疗OA的潜力。值得注意的是，Runx2与所有OA（OR 1.053，95% CI 1.027-1.079；P = 3.95 × 10-5）和KOA（OR 1.043，95% CI 1.001-1.087；P = 0.045）的因果效应在复制研究中重复出现，但支持Runx2表达水平与HOA相关性的证据有限（OR 1.045，95% CI 0.993-1.101；P = 0.094）：我们的分析表明，在所有三种表型中，Runx2表达与OA风险呈正相关，这表明Runx2抑制剂在治疗OA方面具有潜力，并从遗传学角度提供了证据。

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来源期刊

Rheumatology and Therapy RHEUMATOLOGY-

CiteScore

6.00

自引率

5.30%

发文量

审稿时长

6 weeks

期刊介绍： Aims and Scope Rheumatology and Therapy is an international, open access, peer reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world and health outcomes research around the discovery, development, and use of rheumatologic therapies. Studies relating to diagnosis, pharmacoeconomics, public health, quality of life, and patient care, management, and education are also welcomed. Areas of focus include, but are not limited to, rheumatoid arthritis, gout, gouty arthritis, psoriatic arthritis, osteoarthritis, juvenile idiopathic/rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis, Pompe’s disease, inflammatory joint conditions, musculoskeletal conditions, systemic sclerosis, and fibromyalgia. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, case reports, trial protocols, communications and letters. 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