Upon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to increased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI.

激活后，中性粒细胞释放中性粒细胞胞外陷阱 (NET)，这有助于循环 DNA 负荷和血栓形成，包括 ST 段抬高型心肌梗死 (STEMI)。脱氧核糖核酸酶 (DNase) 1 降解循环 DNA 和 NET。较低的 DNase 活性与 NET 负担和梗塞面积相关。损害 DNase 1 功能的 DNase 1 Q222R 单核苷酸多态性 (SNP) 与心肌梗塞有关。我们评估了 Q222R SNP 是否与 STEMI 中增加的 NET 负担有关并影响长期结果。我们招募了 711 名接受经皮冠状动脉介入治疗 (pPCI) 的 STEMI 患者和 1422 名对照。对 DNase 1 Q222R SNP 进行基因分型。在 pPCI 期间，在罪犯部位和外周血浆中测定了 DNase 活性、双链 (ds)DNA 和瓜氨酸化组蛋白 H3。通过针对心血管危险因素调整的多变量 Cox 回归评估 Q222R 变异与心血管和全因死亡率的关系。纯合 Q222R DNase 1 变体存在于 64 名 (9.0%) STEMI 患者中，其频率与对照组相同。Q222R 纯合子患者表现出较低的 DNase 活性和增加的循环 DNA 负荷。在所有患者中，中位生存期为 60 个月。纯合 Q222R 变异与 STEMI 后的心血管和全因死亡率独立相关。dsDNA/DNase 比率独立预测心血管和全因死亡率。这些发现强调了 Q222R DNase 1 SNP 与 NET 负担增加和代偿性 DNase 活性降低有关，并且可能作为 STEMI 后不良结果的独立危险因素。