Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis
Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis
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DOI：
10.1164/rccm.201806-1157oc
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发表时间：
2019-04-01
影响因子：
24.7
通讯作者：
Brunham, Liam R.
中科院分区：
文献类型：
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作者：
Trinder, Mark;Genga, Kelly R.;Brunham, Liam R.
理由：脓毒症期间高密度脂蛋白 (HDL) 胆固醇 (HDL-C) 水平下降，水平较低与生存率较差相关。然而，脓毒症期间 HDL-C 变化的遗传机制，以及与生存的关系是否是因果关系，在很大程度上尚不清楚。 目的：我们假设 HDL 代谢相关基因的变异会导致脓毒症期间 HDL-C 水平和临床结果的变化。 方法：我们对 200 名急诊科收治的脓毒症患者（早期感染队列）进行了 HDL 相关基因的靶向重测序。我们检查了遗传变异与 HDL-C 水平、28 天生存率、90 天生存率、器官功能障碍以及血管加压药或通气支持需求的关系。在 VASST（败血性休克患者输注加压素与去甲肾上腺素试验）队列 (n = 632) 和圣保罗医院重症监护病房 2 (SPHICU2) 队列 (n = 203) 中进一步评估了候选变异。测量和主要结果：我们在 CETP（胆固醇酯转移蛋白基因；rs1800777A）中发现了一种罕见的错义变异，该变异与显着相关。败血症期间 HDL-C 水平降低。与非携带者相比，A 等位基因携带者 (n = 10) 的生存率较低，器官衰竭较多，并且对器官支持的需求更大。我们在 VASST 和 SPHICU2 队列中重复了这一发现，其中 rs1800777-A 携带者（分别为 n = 35 和 n = 12）的 28 天生存率显着降低。孟德尔随机化与遗传性降低的 HDL 水平是脓毒症生存率降低的一个原因一致。结论：我们的结果表明 CETP 是脓毒症期间 HDL 水平和临床结果的关键调节因子。这些数据表明 HDL 在脓毒症中发挥着关键作用。
Rationale: High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown.Objectives: We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis.Methods: We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203).Measurements and Main Results: We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival.Conclusions: Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.