Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
EBioMedicine. 2018 Dec;38:257-264. doi: 10.1016/j.ebiom.2018.11.032. Epub 2018 Nov 23.
Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown.
We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004-2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000-2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival.
In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020).
The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection.
Canadian Institutes of Health Research (PJT-156056).
前蛋白转化酶枯草溶菌素 9（PCSK9）活性降低与感染性休克患者短期死亡率降低有关。PCSK9 基因型是否影响脓毒症幸存者的长期结局尚不清楚。
我们评估了 PCSK9 无功能（LOF）基因型对三级医院脓毒症患者入院后 28 天内 1 年死亡率和感染相关再入院（IRR）的影响。 推导队列纳入了 342 名在 2004 年至 2014 年期间在一家三级医院存活 28 天的脓毒症患者，而独立验证队列纳入了 1079 名在同一家医院入住的感染性休克患者（2000-2006 年）。 所有患者均对三种常见错义 PCSK9 LOF 变体 rs11591147、rs11583680、rs562556 进行基因分型，并根据每位患者 LOF 等位基因的数量将其分为 3 组：野生型、单个 PCSK9 LOF 和多个 PCSK9 LOF。 我们还使用两个队列进行荟萃分析，以研究 PCSK9 基因型对 90 天生存率的影响。
在推导队列中，携带多个 PCSK9 LOF 等位基因的患者复合终点 1 年死亡或 IRR 的风险较低（HR：0.40，P=0.006），中性粒细胞计数下降加速（P=0.010），PCSK9 水平降低（P=0.037）与 WT/single LOF 组相比。 我们的荟萃分析表明，多个 LOF 等位基因的存在与较低的 90 天死亡率风险相关（OR=0.69，P=0.020）。
多个 PCSK9 LOF 等位基因的存在降低了脓毒症幸存者 1 年死亡或 IRR 的风险。 生物学指标表明，这可能与初始感染的快速解决有关。
加拿大卫生研究院（PJT-156056）。
