Lin Kun, Lin Qi, Lv Weifeng, Li Yao, Su Rong
The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, Guangdong, 528000, China.
Department of Laboratory Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, 528000, China.
BMC Rheumatol. 2025 Jun 4;9(1):65. doi: 10.1186/s41927-025-00521-y.
The incidence of rheumatoid arthritis (RA) is rising. However, its pathogenesis has not been fully understood, and the current therapeutic regimens are still limited. The aim of this study was to investigate the causal effect of plasma proteins on RA using Mendelian randomization (MR) analysis.
We performed MR analysis with 4907 plasma protein genetic associations used for exposure and RA genome-wide association data used as outcomes. The method was dominated by Inverse Variance Weighting, in addition to MR-Egger and Weighted Median. Meanwhile, further external validation and reverse MR analysis were conducted to systematically assess the causal relationship between plasma proteins and RA.
Preliminary MR analysis identified two proteins (SPAG11B and DEFB135) associated with RA, and elevated plasma levels of both proteins would reduce the risk of RA (for SPAG11B, OR = 0.49, 95% CI = 0.40-0.61, p = 1.19 × 10; for DEFB135, OR = 0.28, 95% CI = 0.15-0.52, p = 4.51 × 10, using the IVW method). In the external validation phase, the results were reproducible for SPAG11B, but not for DEFB135. Reverse MR analysis pointed out that RA exhibited reverse causality for plasma levels of SPAG11B (OR = 0.93, 95% CI = 0.89-0.98, p = 0.004), but not for DEFB135 (p = 0.93).
The results of MR analysis in this study supported that SPAG11B as a novel biomarker for RA was worthy of further investigation.
类风湿关节炎（RA）的发病率正在上升。然而，其发病机制尚未完全明确，目前的治疗方案仍然有限。本研究旨在利用孟德尔随机化（MR）分析探讨血浆蛋白对RA的因果效应。
我们采用4907个血浆蛋白遗传关联作为暴露因素，以RA全基因组关联数据作为结局进行MR分析。分析方法以逆方差加权法为主，同时采用MR-Egger法和加权中位数法。同时，进行了进一步的外部验证和反向MR分析，以系统评估血浆蛋白与RA之间的因果关系。
初步MR分析确定了两种与RA相关的蛋白（SPAG11B和DEFB135），两种蛋白血浆水平升高均会降低RA风险（使用IVW法，对于SPAG11B，OR = 0.49，95%CI = 0.40 - 0.61，p = 1.19×10；对于DEFB135，OR = 0.28，95%CI = 0.15 - 0.52，p = 4.51×10）。在外部验证阶段，SPAG11B的结果具有可重复性，但DEFB135不具有。反向MR分析指出，RA对SPAG11B的血浆水平存在反向因果关系（OR = 0.93，95%CI = 0.89 - 0.98，p = 0.004），但对DEFB135不存在（p = 0.93）。
本研究的MR分析结果支持SPAG11B作为RA的一种新型生物标志物值得进一步研究。
