DNASE1*2 as a genetic determinant of impaired NET clearance and disease predisposition

Neutrophil extracellular traps (NETs) are essential components of antimicrobial defense, but excessive or persistent NET accumulation can promote inflammation, tissue injury, thrombosis, and disease progression. DNase I is a major extracellular nuclease involved in the degradation of NETs and extracellular DNA, thereby contributing to immune homeostasis. Genetic variation in DNASE1 may influence this clearance capacity. Among DNASE1 polymorphisms, the Q222R substitution, designated DNASE1*2, is a common functional variant associated with reduced DNase I enzymatic activity. This reduction may limit NET degradation under conditions of increased extracellular DNA burden, such as inflammation and malignancy. Clinical studies have linked DNASE1*2 or DNase I phenotype 2 with myocardial infarction, adverse cardiovascular outcomes, and several malignancies. This review summarizes current evidence supporting DNASE1*2 as a potential genetic modifier of DNase I activity, NET clearance, and disease susceptibility. The review also discusses the possible clinical relevance of DNASE1*2 in disease risk, prognosis, and future genotype-informed therapeutic strategies, which require further validation.