Effect of Higher Glycated Hemoglobin (HbA1c) Levels on rheumatoid arthritis Risk:A Mendelian Randomization Study

Abstract

Abstract Introduction：Published studies have suggested a potential association between diabetes mellitus (DM) and RA, with glycated hemoglobin (HbA1c) serving as an important biomarker for DM. The purpose of this study was to investigate the causal relationship between HbA1c levels and RA risk using Mendelian randomization (MR) analysis. methods：A two-sample Mendelian randomization (MR) study was conducted using genetic variants as instrumental variables (IVs) related to HbA1c. Summary statistics from genome-wide association studies (GWAS) were obtained from the publicly accessible Integrative Epidemiology Unit (IEU) OpenGWAS database. A systematic selection process was employed to identify high-quality instrumental single-nucleotide polymorphisms (SNPs) strongly associated with the exposure. Various MR methodologies, such as inverse-variance weighted (IVW) and MR-Egger, were implemented to determine causal effects. The MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were used to evaluate horizontal pleiotropy, heterogeneities, and stability of the association. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Results：A total of 9 SNPs were identified as final IVs. The MR analysis demonstrated a significant causal relationship between elevated HbA1c levels and an increased risk of seronegative RA [odds ratio (OR) = 1.358, 95% confidence interval (CI), 1.044-1.767]. However, no significant evidence of a causal relationship was observed between HbA1c and seropositive RA [OR = 1.033, 95% CI, 0.850-1.257] or overall RA [OR = 1.093, 95% CI, 0.935-1.278]. Sensitivity analyses supported the robustness of the findings, with no significant evidence of heterogeneity or bias and no potential SNPs affecting the causal link. Conclusions:This study provides evidence of a causal relationship between HbA1c levels and seropositive RA risk, emphasizing the importance of closely monitoring and managing HbA1c levels in patients. Further research is needed to elucidate shared pathophysiological mechanisms between DM and RA, which may lead to novel therapeutic strategies.