The Causal Association Between Gestational Diabetes Mellitus and Arthritis: A Bidirectional Two-Sample Mendelian Randomization Analysis

Background: The long-term complications of gestational diabetes mellitus (GDM) may be associated with the development of arthritis, particularly rheumatoid arthritis (RA) and osteoarthritis (OA). However, the possible relationship between these two conditions remains unclear, hindering our understanding of both diseases. We conducted a novel study using bidirectional two-sample Mendelian randomization to explore the potential causal bidirectional relationship between GDM and arthritis. Methods In this study, we extracted single nucleotide polymorphisms closely associated with GDM and arthritis (RA, OA) from published genome-wide association studies (GWAS) data in open databases as instrumental variables (IVs). We employed inverse variance-weighted as the main evaluation criterion, the weighted median method as a possible alternative criterion, and multiple methods as supplements to assess causal relationships. Results were presented as odds ratios (ORs). Additionally, leave-one-out sensitivity analysis, horizontal pleiotropy, and heterogeneity tests were used to verify the reliability and stability of the results. Result Our results indicate a causal association between GDM and an increased risk of arthritis (RA: OR = 4.34, 95% CI = 3.49–5.41, P  = 1.96 × 10– 39 , OA: OR = 1.05, 95% CI = 1.02–1.07, P  = 5.27 × 10 − 05 ). In reverse MR analysis, our findings supported the promoting effect of RA on the development of GDM (OR = 1.15, 95% CI = 1.11–1.20, P  = 4.44 × 10 –14 ), while the evidence is insufficient to support the conclusion that OA affects the development of GDM ( P  = 0.757). The heterogeneity test, horizontal pleiotropy test, and leave-one-out sensitivity analysis demonstrated the reliability and stability of our study's results. Conclusion Our study suggests that genetically predisposed GDM increases the risk of developing arthritis (OA, RA). Additionally, genetically predisposed RA is causally associated with an increased risk of GDM. However, we did not find evidence for a causal association between genetically predisposed OA and GDM. These results contribute to a better understanding of the underlying mechanisms of GDM and arthritis. Furthermore, our study has significant potential to guide clinical management and the prevention of complications in patients with GDM and arthritis.