低密度脂蛋白胆固醇清除率降低与感染性休克死亡率增加有因果关系。

IF 6 1区 医学 Q1 CRITICAL CARE MEDICINE
Nozomi Takahashi, Kyle R Campbell, Taka-Aki Nakada, Keith R Walley
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引用次数: 0

摘要

目的:探讨低密度脂蛋白胆固醇(LDL-C)水平是否与感染性休克28天死亡率有关。设计:我们测量了脓毒性休克患者的LDL-C水平和基因型。利用基因分型和全基因组关联研究总结了来自15万多名日本参与者的统计数据,我们从基因上预测了感染前LDL-C水平。双样本孟德尔随机化用于评估感染前LDL-C水平与28天死亡率之间的因果关系。我们分析了PCSK9和3-羟基-3-甲基戊二酰辅酶a还原酶(HMGCR)基因型,以确定LDL-C清除或产生是否是潜在的机制。设置:日本多中心icu。患者:基因分型感染性休克患者(n = 614)。干预措施:没有。测量结果和主要结果:感染前预测的LDL-C水平远高于感染性休克开始时直接测量的LDL-C水平(141 mg/dL vs 40 mg/dL, p < 0.001)。双样本孟德尔随机化显示,感染前LDL-C水平高与感染性休克28天死亡率增加有因果关系(风险比,2.78;P = 0.039)。通过LDL受体增加LDL- c清除率的PCSK9遗传变异(遗传代理PCSK9抑制剂治疗)与降低死亡率相关(p = 0.003),而降低LDL- c产生的HMGCR遗传变异(遗传代理他汀类药物治疗)与降低感染性休克死亡率无关(实际上观察到相反的效果,p = 0.039)。导致感染前LDL- c水平升高和死亡率升高的两个主要遗传变异是载脂蛋白基因(ApoB100-rs13306206和ApoE-rs7412),载脂蛋白参与LDL- c与LDL受体的结合。结论:低LDL-C清除率解释了高遗传预测感染前LDL-C水平与感染性休克死亡率增加之间的因果关系。PCSK9、ApoB和ApoE变异被确定为因果关系,它们都与LDL受体或其与LDL- c的相互作用有关。加强LDL受体介导的病原体脂质毒素清除可能改善感染性休克的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Decreased Clearance of Low-Density Lipoprotein Cholesterol is Causally Associate With Increased Mortality of Septic Shock.

Objective: To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality.

Design: We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism.

Setting: Multicenter ICUs in Japan.

Patients: Genotyped septic shock patients (n = 614).

Interventions: None.

Measurements and main results: Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality (p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes (ApoB100-rs13306206 and ApoE-rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor.

Conclusions: Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9, ApoB, and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes.

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来源期刊
Critical Care Medicine
Critical Care Medicine 医学-危重病医学
CiteScore
16.30
自引率
5.70%
发文量
728
审稿时长
2 months
期刊介绍: Critical Care Medicine is the premier peer-reviewed, scientific publication in critical care medicine. Directed to those specialists who treat patients in the ICU and CCU, including chest physicians, surgeons, pediatricians, pharmacists/pharmacologists, anesthesiologists, critical care nurses, and other healthcare professionals, Critical Care Medicine covers all aspects of acute and emergency care for the critically ill or injured patient. Each issue presents critical care practitioners with clinical breakthroughs that lead to better patient care, the latest news on promising research, and advances in equipment and techniques.
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