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Published on: August 8, 2019
Tumor necrosis factor mediates the impact of PM2.5 on bone mineral density: Inflammatory proteome Mendelian
Mingzheng Li1, Peng Shi1, Huajie Yang1
1Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China; Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China.
Abstract:
To assess the causal effect of particulate matter 2.5 (PM2.5) on human bone mineral density (BMD) and to explore the possible mechanism and proportion mediated by inflammation-related protein. The genetic correlation between PM2.5 and BMD was assessed using the Linkage Disequilibrium Score (LDSC), and the causal effect between PM2.5 and BMD was assessed by two-sample Mendelian randomization (TSMR). A 2-step Mendelian randomization (MR) approach was employed to evaluate the potential role of inflammation-associated protein as the mediator in the causal association between PM2.5 and BMD. The multivariate Mendelian randomization (MVMR) study was designed to perform mediation analyses, exclude possible confounders and calculate the proportion of mediation. Subsequently, we used Bayesian colocalization analysis to consolidate the MR results. Finally, using drug-target MR design, we evaluated the potential repurposing of tumor necrosis factor (TNF) inhibitors for the treatment of osteoporosis (OP). The results of the analyses show that BMD is negatively influenced by PM2.5 (Inverse variance weighted [IVW] beta [β] = -0.288, 95% confidence interval [CI]: -0.534 - -0.042, P < 0.05). PM2.5 has a positive causal association with TNF (IVW β = 1.564, 95% CI: 0.155 - 2.973, P < 0.05) and a negative causal association with protachykinin-1 (TAC-1) (IVW β = -1.654, 95% CI: -3.063 - -0.244, P < 0.05). TNF has a negative causal association with BMD (Wald ratio β = -0.082, 95% CI: -0.165 - 0.000, P < 0.05) and TAC-1 has a positive causal association with BMD (IVW β = 0.042, 95% CI: 0.007 - 0.077, P < 0.05). After adjusting TNF and TAC-1, PM2.5 has no causal association with BMD (IVW β = -0.200, 95% CI: -0.579 - 0.179, P > 0.05). After adjusting PM2.5 and TAC-1, there was still a negative causal association between TNF and BMD (IVW β = -0.089, 95% CI: -0.166 - -0.012, P < 0.05). In the final drug-target MR study, the protective effect of TNF/TNF receptor 1 (TNFR1) inhibition on BMD was observed. For every 10% decrease of circulating C-reactive protein (CRP) achieved by TNF/TNF receptor 1 (TNFR1) blockade, β was 0.540 (95% CI: 0.040-1.040) for BMD. We found a negative causal association between PM2.5 and BMD and that causal association was mediated by TNF. The results of drug-target MR do support TNFR1 as a promising target for OP prevention among the general population.
Insights
Exposure to fine particulate matter (PM2.5) negatively impacts bone mineral density (BMD), with this effect mediated by tumor necrosis factor (TNF). Targeting TNF or its receptor (TNFR1) may offer a promising strategy for preventing osteoporosis (OP).
Area of Science:
- Environmental Health Sciences
- Genetics
- Rheumatology
Background:
- Particulate matter 2.5 (PM2.5) exposure is a global concern.
- Its impact on bone mineral density (BMD) and the underlying mechanisms require elucidation.
- Inflammation-associated proteins may play a role in PM2.5-induced bone loss.
Purpose of the Study:
- To determine the causal effect of PM2.5 on BMD.
- To investigate the mediating role of inflammation-related proteins, specifically tumor necrosis factor (TNF) and protachykinin-1 (TAC-1).
- To explore the potential of TNF inhibitors for osteoporosis (OP) prevention.
Main Methods:
- Two-sample Mendelian randomization (TSMR) and multivariate Mendelian randomization (MVMR) were employed.
- Linkage Disequilibrium Score (LDSC) assessed genetic correlation.
- Bayesian colocalization and drug-target MR analyses were utilized.
Main Results:
- PM2.5 showed a negative causal association with BMD (β = -0.288).
- PM2.5 causally influenced TNF (β = 1.564) and TAC-1 (β = -1.654).
- TNF mediated the association between PM2.5 and BMD; TAC-1 did not.
- TNF inhibition demonstrated a protective effect on BMD, suggesting TNFR1 as a potential therapeutic target for OP.
Conclusions:
- PM2.5 exposure causally reduces BMD.
- The observed effect is significantly mediated by TNF.
- Targeting TNF/TNFR1 presents a viable therapeutic avenue for osteoporosis prevention.
