Genetically predicted inflammatory cytokines and bone health outcomes: A 2-sample Mendelian randomization study

Circulating inflammatory factors have been implicated in various bone health outcomes, but the causal relationships remain unclear. We applied 2-sample Mendelian randomization to investigate the effects of 41 inflammatory factors on 5 bone health outcomes: osteoarthritis (OA), knee osteoarthritis (KOA), hip osteoarthritis, osteoporosis (OP), and rheumatoid arthritis (RA). We used publicly available summary statistics from genome-wide association studies of inflammatory factors and bone health outcomes. We selected genetic instruments for each inflammatory factor based on the largest available study, and performed inverse-variance weighted (IVW), Mendelian randomization-Egger, and weighted median analyses to estimate the causal effects. We also performed sensitivity analyses to assess the potential impact of horizontal pleiotropy, heterogeneity, and linkage disequilibrium. Genetically predicted IP-10 was associated with a higher odds of OA, and GROA was associated with a slightly higher odds of OP; 5 other cytokines showed inverse associations with selected outcomes in the IVW analysis (IP-10-OA, odds ratio [OR]: 1.09, 95% confidence interval [CI]: 1.01-1.17, P = .037; G-CSF-KOA, OR: 0.91, 95% CI: 0.86-0.96, P = .0006; SCF-HOA, OR: 0.90, 95% CI: 0.83-0.97, P = .004; GROA-OP,OR: 1.002,95% CI: 1.000-1.004,P = .014; MIP-1β-OP, OR: 0.999, 95% CI: 0.998-1.000, P = .031; IL-5-RA, OR: 0.91, 95% CI: 0.83-0.98, P = .019; PDGF-BB-RA, OR: 0.89, 95% CI: 0.80-0.98, P = .022). Across sensitivity analyses, we found no strong evidence of directional pleiotropy for these associations. This 2-sample Mendelian randomization study suggests several genetically predicted associations between inflammatory cytokines and bone health outcomes; however, given the small effect sizes and the limited sample sizes of the exposure genome-wide association studies, larger cytokine genome-wide association studies and independent validation are needed before clinical translation.