Mendelian randomization study of the causal relationship between autoimmune diseases and anemia using proteomic and...

Observational studies have suggested a potential association between autoimmune diseases and anemia, but the direction of causality remains unclear. To investigate the potential causal relationship between autoimmune diseases and anemia using Mendelian randomization (MR).

We conducted a bidirectional two-sample MR study using summary-level genetic data from the EBI and FinnGen databases. We examined 21 autoimmune diseases as exposures and anemia as the outcome, and vice versa. Multivariable MR, meta-analysis, and two-step mediation analysis involving 43 candidate mediators were also performed. Proteomic MR and colocalization analyses were used to validate causal relationships involving proteins. Functional annotations including KEGG pathway, GO enrichment, protein-protein interaction networks, and drug enrichment analyses were performed to identify potential therapeutic targets.

Genetically determined type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and primary biliary cholangitis (PBC) were associated with an increased risk of anemia (P < 0.05 in meta-analysis). Reverse MR analyses suggested potential bidirectional causality between anemia and mixed connective tissue disease, hypothyroidism, and asthma. Mediation analysis indicated that hypothyroidism may contribute to anemia by elevating IgG levels. Proteomic and colocalization analyses identified several proteins associated with anemia (e.g., MCCD1, TMEM106B), T1DM (e.g., CTRB1, CTRB2, IL7RA), RA (e.g., TGFBI, IL1RN), and PBC (e.g., ALDH2, CXCL16).

This MR study supports a causal effect of certain autoimmune diseases on anemia risk and highlights potential protein targets for intervention, offering new insights for anemia prevention and treatment.