Effects of circulating inflammatory proteins on osteoporosis and fractures: evidence from genetic correlation and Mendelian randomization study

Front Endocrinol (Lausanne). 2024 May 1:15:1386556. doi: 10.3389/fendo.2024.1386556. eCollection 2024.

Abstract

Objective: There is a controversy in studies of circulating inflammatory proteins (CIPs) in association with osteoporosis (OP) and fractures, and it is unclear if these two conditions are causally related. This study used MR analyses to investigate the causal associations between 91 CIPs and OP and 9 types of fractures.

Methods: Genetic variants data for CIPs, OP, and fractures were obtained from the publicly available genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary analysis, pleiotropy, and heterogeneity tests to analyze the validity and robustness of causality and reverse MR analysis to test for reverse causality.

Results: The IVW results with Bonferroni correction indicated that CXCL11 (OR = 1.2049; 95% CI: 1.0308-1.4083; P = 0.0192) can increase the risk of OP; IL-4 (OR = 1.2877; 95% CI: 1.1003-1.5070; P = 0.0016), IL-7 (OR = 1.2572; 95% CI: 1.0401-1.5196; P = 0.0180), IL-15RA (OR = 1.1346; 95% CI: 1.0163-1.2668; P = 0.0246), IL-17C (OR = 1.1353; 95% CI: 1.0272-1.2547; P = 0.0129), CXCL10 (OR = 1.2479; 95% CI: 1.0832-1.4377; P = 0.0022), eotaxin/CCL11 (OR = 1.1552; 95% CI: 1.0525-1.2678; P = 0.0024), and FGF23 (OR = 1.9437; 95% CI: 1.1875-3.1816; P = 0.0082) can increase the risk of fractures; whereas IL-10RB (OR = 0.9006; 95% CI: 0.8335-0.9730; P = 0.0080), CCL4 (OR = 0.9101; 95% CI: 0.8385-0.9878; P = 0.0242), MCP-3/CCL7 (OR = 0.8579; 95% CI: 0.7506-0.9806; P = 0.0246), IFN-γ [shoulder and upper arm (OR = 0.7832; 95% CI: 0.6605-0.9287; P = 0.0049); rib(s), sternum and thoracic spine (OR = 0.7228; 95% CI: 0.5681-0.9197; P = 0.0083)], β-NGF (OR = 0.8384; 95% CI: 0.7473-0.9407; P = 0.0027), and SIRT2 (OR = 0.5167; 95% CI: 0.3296-0.8100; P = 0.0040) can decrease fractures risk.

Conclusion: Mendelian randomization (MR) analyses indicated the causal associations between multiple genetically predicted CIPs and the risk of OP and fractures.

Keywords: Mendelian randomization; bone homeostasis; circulating inflammatory proteins; fracture; osteoporosis.

MeSH terms

  • Female
  • Fibroblast Growth Factor-23
  • Fractures, Bone / blood
  • Fractures, Bone / epidemiology
  • Fractures, Bone / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Mendelian Randomization Analysis*
  • Osteoporosis* / blood
  • Osteoporosis* / genetics
  • Osteoporotic Fractures / blood
  • Osteoporotic Fractures / epidemiology
  • Osteoporotic Fractures / genetics
  • Polymorphism, Single Nucleotide

Substances

  • FGF23 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The Natural Science Foundation of Fujian Province (No. 2021J02035) and Fujian Provincial Health Technology Project (No. 2020CXA039) supported this study.