Causal association between neutrophil extracellular traps and rheumatoid arthritis: A 2-sample bidirectional Mendelian randomization study

This study explores the causal association between neutrophil extracellular traps and rheumatoid arthritis (RA). A 2-sample bidirectional Mendelian randomization (MR) analysis was performed. The primary analyses were performed using the inverse variance weighted method, with confirmation using the weighted median, weighted mode, and MR-Egger methods. Heterogeneity was detected using Cochran's Q-test, pleiotropy using MR-Egger regression, and outliers using Mendelian randomization pleiotropy residual sum and outlier. The leave-one-out method was used to determine whether a single single-nucleotide polymorphism drove the results. Using RA as the outcome, a causal link emerged between neutrophil count and RA. Notably, substantial heterogeneity and the detection of outliers for neutrophil count led to the attenuation of this causal association post-correction, but the weighted median and weighted mode analyses hinted at a potential causal relationship. Causal effects of RA were seen on neutrophil count, tumor necrosis factor-α, IL-5, IL-13, and myeloperoxidase. Mendelian randomization pleiotropy residual sum and outlier identified outliers in neutrophil count, yet the causal link persisted following correction. No weak instrumental bias was observed. No horizontal pleiotropy was observed. The leave-one-out analysis showed that no single single-nucleotide polymorphism was driving the results. Neutrophil extracellular traps had no causal associations on RA, but RA had causal associations on neutrophil count, tumor necrosis factor-α levels, IL-5, IL-13, and myeloperoxidase.