Department of Rheumatology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
J Orthop Surg Res. 2024 Sep 11;19(1):559. doi: 10.1186/s13018-024-05034-x.
Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes.
A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data.
The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA.
Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.
骨关节炎（OA）是一种退行性骨关节疾病，涉及遗传易感性。风险变异如何通过其对蛋白质的影响来赋予 OA 的风险仍知之甚少。因此，我们旨在为 OA 及其亚型发现新的有效药物靶点。
基于 OA 及其亚型全基因组关联研究（GWAS）汇总数据集和蛋白质数量性状基因座（pQTL）数据进行全蛋白质组关联研究（PWAS）。随后，进行孟德尔随机化（MR）和共定位分析，以估计蛋白质与 OA 风险之间的关联。在人类血浆 pQTL 数据的独立数据集上进行了复制分析。
七种蛋白质的丰度与 OA 分别存在因果关系，两种蛋白质与膝骨关节炎存在因果关系，六种蛋白质与髋骨关节炎存在因果关系。我们使用独立的 pQTL 数据集复制了其中的 2 个蛋白质。通过共定位的进一步支持，以及更高的 ECM1 水平与 OA 和髋骨关节炎的更高风险存在因果关系。更高的 PCSK1 水平与 OA 的较低风险存在因果关系。较高的 ITIH1、EFEMP1 和 ERLEC1 水平与髋骨关节炎风险降低相关。
我们的研究为 OA 中蛋白质丰度的遗传成分提供了新的见解，并为未来药物开发提供了有前途的治疗靶点。
