PADI4 minor haplotype as risk factor for excessive NET formation and associated wound healing disorders in diabetes mellitus

Diabetes mellitus (DM) is associated with impaired wound healing, partly driven by excessive neutrophil extracellular trap (NET) formation mediated by peptidyl-arginine deiminase 4 (PADI4). While circulating NET markers predict poor healing outcomes, they likely reflect established tissue damage and offer limited opportunity for early intervention. We therefore investigated the association between PADI4 haplotypes, PADI4 expression, NET formation, and clinical outcomes, namely infections and delayed wound and bone healing, in 687 surgical patients (44.7% with DM). Pre-surgical PADI4 expression was 9.4-fold higher in patients with DM, particularly in those who developed wound healing complications. Neutrophils carrying the PADI4 minor haplotype showed increased PADI4 mRNA and protein expression and produced larger quantities of NETs more rapidly than those with the major haplotype. Clinically, patients with DM carrying the minor haplotype had the highest rates of delayed wound healing and infections. Together, these results demonstrate that PADI4 genetic variation influences neutrophil behavior and clinical outcomes. PADI4 haplotyping may provide a clinically actionable biomarker to identify patients with DM at high risk for wound healing complications and guide early preventive strategies.