Repurposing Antidiabetic Drugs for Rheumatoid Arthritis among an East Asian Population: Results from a Two-Sample Mendelian Randomization Study

Background: The time-consuming process of drug development contributes to unmet healthcare needs for rheumatoid arthritis (RA). Studies of Western populations suggest the potential use of antidiabetic drugs as an alternative to lower RA risk. We aimed to examine the possibility of repurposing antidiabetic drugs for RA by evaluating their causal associations with genetic antidiabetic drug target genes using Mendelian randomization (MR) of samples from an East Asian biobank.Methods: We conducted drug-targeting two-sample MR to estimate the association between the antidiabetic drug and RA risk using summary statistics of genome-wide association studies (GWAS). Six single-nucleotide polymorphisms (SNPs) were selected as independent genetic variants that encode the target proteins of the selected antidiabetic drugs (insulin/insulin analogues, thiazolidinediones, and sulfonylureas). Instrumental associations with fasting blood glucose and RA were extracted from the KoGES (Korean Genome and Epidemiology Study) and BBJ (BioBank Japan), respectively.Results: A decrease in fasting blood sugar level of 1 mmol (1.8 mg/dL) by the rs1801282 SNP in the PPARG gene reduced the incidence of RA by about 20%. Moreover, another SNP within the PPARG gene, rs35240997, reduced the incidence of RA about 16%.Conclusion: SNPs within the anti-diabetic drug target genes lowered fasting blood sugar levels and the risk of RA. However, the results from this study require cautious interpretations due to weak instrument bias.