Background Evidence for the association between rheumatoid arthritis (RA) and osteoporosis (OP) remains inconsistent, and the role of inflammatory cytokines in mediating this association remains unclear. Methods This study used linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), and colocalization analyses to assess the association between RA and OP. Mediation MR analysis was conducted to explore the mediating role of inflammatory cytokines. Multitrait analysis of GWAS enhanced statistical power and identified novel genetic associations. Independent risk loci were examined using GCTA-COJO, PLACO, and FUMA analyses. Risk-associated genes were identified by integrated MAGMA, SMR, and TWAS methods, while BLISS analysis revealed relevant proteins. The GEO database was used to validate pleiotropic gene expression. Results Genetic correlation (rg = 0.171), causal association (OR = 1.103), and colocalization analysis (PPH4 = 0.99) together confirmed a genetic link between RA and OP. Interleukin (IL)-17 mediated the RA-OP association. The SNPs rs11574914 and rs11889341 are MTAG-RA independent risk loci. Twenty-five RA-related risk genes are specifically expressed in the lymph node and tonsils. FCRL3 regulates the RA immune infiltration microenvironment. Conclusions IL-17 promotes the progression of RA to OP; FCRL3 regulates the immune infiltration microenvironment of RA and is a potential therapeutic target.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="justify" colname="c1" colnum="1" /> <colspec align="justify" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> Key Points • Genetic correlation, MR, and colocalization analyses confirm a shared genetic basis between RA and OP. • IL-17 is identified as a key inflammatory mediator driving the progression from RA to OP. • Multi-trait GWAS and integrative post-GWAS analyses uncover novel RA-specific loci and 25 immune-related risk genes. • FCRL3 regulates immune cell infiltration in RA and emerges as a potential therapeutic target for inflammation-induced bone loss. </entry> </row> </tbody> </tgroup> </Table>

Inflammatory cytokines mediate the common genetic and immunological background between rheumatoid arthritis and osteoporosis

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2025年11月7日

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Jianguo Zhou,
Xiaoyan Dou,
Xize Wu,
Yue Li,
Shixuan Wang,
Jian Kang

摘要

Background

Evidence for the association between rheumatoid arthritis (RA) and osteoporosis (OP) remains inconsistent, and the role of inflammatory cytokines in mediating this association remains unclear.

Methods

This study used linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), and colocalization analyses to assess the association between RA and OP. Mediation MR analysis was conducted to explore the mediating role of inflammatory cytokines. Multitrait analysis of GWAS enhanced statistical power and identified novel genetic associations. Independent risk loci were examined using GCTA-COJO, PLACO, and FUMA analyses. Risk-associated genes were identified by integrated MAGMA, SMR, and TWAS methods, while BLISS analysis revealed relevant proteins. The GEO database was used to validate pleiotropic gene expression.

Results

Genetic correlation (rg = 0.171), causal association (OR = 1.103), and colocalization analysis (PPH4 = 0.99) together confirmed a genetic link between RA and OP. Interleukin (IL)-17 mediated the RA-OP association. The SNPs rs11574914 and rs11889341 are MTAG-RA independent risk loci. Twenty-five RA-related risk genes are specifically expressed in the lymph node and tonsils. FCRL3 regulates the RA immune infiltration microenvironment.

Conclusions

IL-17 promotes the progression of RA to OP; FCRL3 regulates the immune infiltration microenvironment of RA and is a potential therapeutic target.

Key Points

• Genetic correlation, MR, and colocalization analyses confirm a shared genetic basis between RA and OP.

• IL-17 is identified as a key inflammatory mediator driving the progression from RA to OP.

• Multi-trait GWAS and integrative post-GWAS analyses uncover novel RA-specific loci and 25 immune-related risk genes.

• FCRL3 regulates immune cell infiltration in RA and emerges as a potential therapeutic target for inflammation-induced bone loss.