Abstract
BACKGROUND: Previous epidemiological observational studies have indicated an association between type 1 diabetes (T1DM) and systemic sclerosis (SSc). However, the potential causal relationship between T1DM and SSc remains unclear. Therefore, this Mendelian randomization (MR) study aims to investigate the bidirectional causal relationship between T1DM and SSc through a bidirectional two-sample mendelian randomization analysis. METHODS: We utilized SNP data aggregated from previously published genome-wide association studies (GWAS) and selected appropriate SNPs as instrumental variables (IVs). To explore the bidirectional causal relationship between T1DM and SSc, we conducted bidirectional Mendelian randomization analyses using various methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode approaches. Additionally, sensitivity analyses were performed to further validate the accuracy of the MR results. RESULTS: Our MR analysis using 66 SNPs as IVs for T1DM showed a genetically determined association with an increased risk of SSc (IVW OR = 1.294, 95% CI 1.140-1.469, p < 0.001), consistent across MR-Egger, weighted median, and weighted mode methods, with no evidence of horizontal pleiotropy or heterogeneity, and robustness confirmed by leave-one-out analysis. Conversely, reverse MR analysis using 7 SNPs for SSc revealed no significant association with T1DM (IVW OR = 0.998, 95% CI 0.979-1.016, P = 0.798), consistent across all methods, with no evidence of pleiotropy or heterogeneity, and results confirmed as robust. CONCLUSION: This pioneering mendelian randomization study reveals a causal link between genetic susceptibility to T1DM and an increased risk of SSc, though not vice versa, emphasizing the need for validation across diverse populations and further exploration of underlying mechanisms.