Repurposing antidiabetic drugs for rheumatoid arthritis: results from a two-sample Mendelian randomization study

Abstract

Despite increasing therapeutic options to treat rheumatoid arthritis (RA), many patients fail to reach treatment targets. The use of antidiabetic drugs like thiazolidinediones has been associated with lower RA risk. We aimed to explore the repurposing potential of antidiabetic drugs in RA prevention by assessing associations between genetic variation in antidiabetic drug target genes and RA using Mendelian randomization (MR). A two-sample MR design was used to estimate the association between the antidiabetic drug and RA risk using summary statistics from genome-wide association studies (GWAS). We selected independent genetic variants from the gene(s) that encode the target protein(s) of the investigated antidiabetic drug as instruments. We extracted the associations of instruments with blood glucose concentration and RA from the UK Biobank and a GWAS meta-analysis of clinically diagnosed RA, respectively. The effect of genetic variation in the drug target(s) on RA risk was estimated by the Wald ratio test or inverse-variance weighted method. Insulin and its analogues, thiazolidinediones, and sulfonylureas had valid genetic instruments (n = 1, 1, and 2, respectively). Genetic variation in thiazolidinedione target (gene: PPARG) was inversely associated with RA risk (odds ratio [OR] 0.38 per 0.1mmol/L glucose lowering, 95% confidence interval [CI] 0.20–0.73). Corresponding ORs (95%CIs) were 0.83 (0.44–1.55) for genetic variation in the targets of insulin and its analogues (gene: INSR), and 1.12 (0.83, 1.49) 1.25 (0.78-2.00) for genetic variation in the sulfonylurea targets (gene: ABCC8 and KCNJ11). In conclusion, genetic variation in the thiazolidinedione target is associated with a lower RA risk. The underlying mechanisms warrant further exploration.

Causal associations of male infertility with stroke: a two-sample Mendelian randomization study

“…This screening involved considering a genome-wide significance level of p < 5×10 −6 , ensuring that only highly significant SNPs were included in the analysis ( 14 ). To ensure the independence of SNPs for MR analyses, a linkage disequilibrium clumping algorithm was employed to identify SNPs that exhibit minimal correlation with each other ( r 2 <0.001) ( 15 ). Furthermore, the F statistic was used to evaluate the potential bias caused by weak instruments.…”

Thyroid function and epilepsy: a two-sample Mendelian randomization study

“…In addition, other methods, including Wald ratio, MR-Egger, weighted median, and weighted mode, were also employed. Wald ratio method was performed when only one IV was obtained ( Qin et al, 2023 ). The MR-Egger method could be used to assess potential pleiotropy by evaluating the intercept ( Ren et al, 2023 ).…”

Therapeutic potential of Coptis chinensis for arthritis with underlying mechanisms

“…However, the types of arthritis treated with these targets are not completely clear. Targets, β2-adrenergic receptor (ADRB2), AHR, CRP, IRF1, prostaglandin G/H synthase 1 (PTGS1), SPP1 and other targets, exert key effects in the pathogenesis of arthritis, but role of them in the treatment of arthritis with CC has not been confirmed ( Table 3 ) ( Xu et al, 2004 ; Koskela et al, 2012 ; Ko et al, 2013 ; Li et al, 2013 ; Xue et al, 2014 ; Song et al, 2016 ; Trzybulska et al, 2018 ; Bonelli et al, 2019 ; Chu et al, 2019 ; Lin et al, 2019 ; Sun et al, 2020 ; Orecchini et al, 2020 ; Yang et al, 2020 ; Nalesso et al, 2021 ; Tang et al, 2021 ; Xu and Xu, 2021 ; Zou et al, 2021 ; Balasundaram et al, 2022 ; Cai et al, 2022 ; Liu et al, 2022 ; Wang et al, 2022 ; Zhang et al, 2022 ; Zhang et al, 2022 ; Han et al, 2022 ; Man et al, 2022 ; Nguyen et al, 2022 ; Qian et al, 2022 ; Tavallaee et al, 2022 ; Zhuang et al, 2022 ; Afnan et al, 2023 ; Baggio et al, 2023 ; Sun et al, 2023b ; Zhou et al, 2023 ; Fan et al, 2023 ; Huang et al, 2023 ; Ning et al, 2023 ; Qin et al, 2023 ; Skougaard et al, 2023 ; Tu et al, 2023 ; Xie et al, 2023 ; Yan et al, 2023 ; Yu et al, 2023 ; Zhao et al, 2023 ). We have elaborated on the role of targets such as MMP-3, IL-1β, MAPK, IL-6, ADRB2, AHR, CRP, CAV1, CXCL2, SPP1 and other targets in treating arthritis, explored the potential targets and mechanisms of CC in treating arthritis, analyzed the feasibility of CC as an anti-arthritis drug, and provided a theoretical basis for subsequent research.…”