Mendelian randomization to evaluate the causal relationship between liver enzymes and the risk of six specific bone and joint-related diseases

Front Immunol. 2023 Aug 16:14:1195553. doi: 10.3389/fimmu.2023.1195553. eCollection 2023.

Abstract

Background: Studies of liver dysfunction in relation to bone and joint-related diseases are scarce, and its causality remains unclear. Our objective was to investigate whether serum liver enzymes are causally associated with bone and joint-related diseases using Mendelian randomization (MR) designs.

Methods: Genetic data on serum liver enzymes (alkaline phosphatase (ALP); alanine transaminase (ALT); gamma-glutamyl transferase (GGT)) and six common bone and joint-related diseases (rheumatoid arthritis (RA), osteoporosis, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and gout) were derived from independent genome-wide association studies of European ancestry. The inverse variance-weighted (IVW) method was applied for the main causal estimate. Complementary sensitivity analyses and reverse causal analyses were utilized to confirm the robustness of the results.

Results: Using the IVW method, the positive causality between ALP and the risk of osteoporosis diagnosed by bone mineral density (BMD) at different sites was indicated (femoral neck, lumbar spine, and total body BMD, odds ratio (OR) [95% CI], 0.40 [0.23-0.69], 0.35 [0.19-0.67], and 0.33 [0.22-0.51], respectively). ALP was also linked to a higher risk of RA (OR [95% CI], 6.26 [1.69-23.51]). Evidence of potential harmful effects of higher levels of ALT on the risk of hip and knee OA was acquired (OR [95% CI], 2.48 [1.39-4.41] and 3.07 [1.49-6.30], respectively). No causal relationship was observed between GGT and these bone and joint-related diseases. The study also found that BMD were all negatively linked to ALP levels (OR [95% CI] for TBMD, FN-BMD, and LS-BMD: 0.993 [0.991-0.995], 0.993 [0.988-0.998], and 0.993 [0.989, 0.998], respectively) in the reverse causal analysis. The results were replicated via sensitivity analysis in the validation process.

Conclusions: Our study revealed a significant association between liver function and bone and joint-related diseases.

Keywords: Mendelian randomization; bone and joint-related diseases; causality; genome-wide association studies; liver enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase
  • Alkaline Phosphatase / genetics
  • Arthritis, Rheumatoid*
  • Coloring Agents
  • Genome-Wide Association Study
  • Humans
  • Liver
  • Mendelian Randomization Analysis
  • Osteoarthritis, Knee*
  • Osteoporosis* / genetics
  • gamma-Glutamyltransferase

Substances

  • Alanine Transaminase
  • gamma-Glutamyltransferase
  • Alkaline Phosphatase
  • Coloring Agents

Grants and funding

This study was supported by the National Natural Science Foundation of China (81972049, 82172467, 82172406), the First Affiliated Hospital of Sun Yat-Sen University Ke Ling Funding Program for Novel and Distinguished Talents (R07005), and the Guangdong Natural Science Funds for Distinguished Young Scholar of China (2021B1515020008).