Arterial hypertension is associated with the DNase I single nucleotide polymorphism Q222R and enhanced neutrophil extracellular trap formation

 

Background:

DNase I degrades neutrophil extracellular traps (NETs), an important effector mechanism of polymorphonuclear cells (PMNs). The Q222R single nucleotide polymorphism (SNP) in the DNase I gene impairs its function significantly. This SNP is associated with a higher incidence of myocardial infarction. In a model of spontaneously hypertensive rats, DNase I activity is decreased. We hypothesized that 1) Q222R is associated with hypertension and decreased NET degradation and 2) that high blood pressure (RR) leads to increased NET formation.

Methods:

DNA (n = 274, male = 77%, age = 59 ± 13y) and PMNs (n = 18, male = 78%, age = 64 ± 10y) were isolated from STEMI patients at the Medical University of Vienna. Q222R SNP (ID rs 105384) was analyzed by reaction restriction fragment length PCR. PMNs were stimulated with 2.5µM phorbol-12-myristate-13-acetate (PMA) and NET formation was measured using a fluorescence reader-based quantification assay.

Results:

Hypertension was more common in patients with a homozygous Q222R SNP (84% vs. 62%, p = 0.046). In patients with hypertension, both systolic and diastolic RR were positively correlated with NET formation after stimulation with PMA (systolic r = 0.479, p = 0.044; diastolic r = 0.600, p = 0.008).

Conclusion:

Impaired DNase I activity leads to increased levels of extracellular DNA, a danger-associated molecular pattern (DAMP) which leads to chronic inflammation. This results in higher systemic blood pressure, which also fosters the proinflammatory milieu by ROS-mediated activation of PMNs.