Causal association between type 1 diabetes and autoimmune cholestasis: A bi-directional Mendelian randomized study

Explore the causal relationship of risk between type 1 diabetes and primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). A causal association between type 1 diabetes and autoimmune liver disease remains ambiguous. This study explored potential causality between different autoimmune conditions, indicating that caution should be taken of the occurrence of autoimmune liver diseases in daily management of T1D patients. Genetic variants were extracted as instrumental variables from the genome-wide association study (GWAS) of PBC, PSC, type 1 diabetes (T1D), and type 2 diabetes (T2D). Associations between four primary liver enzymes, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transferase (ALT), and glutamyl transaminase (GGT), and blood glucose-related indicators such as 2h-glucose post-challenge (2hGlu), fasting glucose (FG), fasting insulin (FI), and glycated hemoglobin (HbA1c) were also evaluated (GWAS p-value < 5 × 10^-8). A bi-directional two-sample Mendelian randomization (MR) design was used to assess causality between type 1 diabetes and autoimmune cholestasis. Genetic susceptibility to T1D increased the risk of PSC and PBC. Genetic susceptibility to T2D reduced the risk of PSC and showed no correlation with PBC. Genetically susceptibility to PBC increased the risk of T1D and showed no correlation with T2D. Genetically susceptibility to PSC did not impact the risk of T1D and T2D. T1D patients have an increased risk of PBC/PSC, but such causation is not mediated or explained by the altered blood glucose levels. A bi-directional causal association was identified between type 1 diabetes and autoimmune cholestasis. The findings provide new insight into the management of patients with these conditions.