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. 2025 Jun 4;9(1):65.
doi: 10.1186/s41927-025-00521-y.

SPAG11B, a potential biomarker for rheumatoid arthritis: a two-sample bidirectional Mendelian randomization analysis

Kun Lin  1   2 , Qi Lin  1   2 , Weifeng Lv  1   2 , Yao Li  1   2 , Rong Su  3   4
Affiliations

SPAG11B, a potential biomarker for rheumatoid arthritis: a two-sample bidirectional Mendelian randomization analysis

Kun Lin et al. BMC Rheumatol. .

Abstract

Background: 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.

Methods: 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.

Result: 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- 10; for DEFB135, OR = 0.28, 95% CI = 0.15-0.52, p = 4.51 × 10- 5, 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).

Conclusion: The results of MR analysis in this study supported that SPAG11B as a novel biomarker for RA was worthy of further investigation.

Keywords: DEFB135; Mendelian randomization; Plasma protein; Rheumatoid arthritis; SPAG11B.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study is a secondary analysis of publicly available GWAS datasets that have prior ethical approval, so no informed consent or ethical approval is required for this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of MR analysis revealing causality from plasma proteins on RA. MR, Mendelian Randomization; FDR, false discovery rate; RA, rheumatoid arthritis
Fig. 2
Fig. 2
Volcano plot of MR analysis for 4907 plasma proteins on RA risk
Fig. 3
Fig. 3
A MR analysis estimated the causal effect of SPAG11B on RA. B Scatterplot derived from MR on the potential of SPAG11B to predict RA
Fig. 4
Fig. 4
A MR analysis estimated the causal effect of DEFB135 on RA. B Scatterplot derived from MR on the potential of DEFB135 to predict RA
Fig. 5
Fig. 5
A MR analysis estimated the association of SPAG11B with RA from IEU. B MR analysis estimated the association of SPAG11B with RA from UKB
See this image and copyright information in PMC

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