Mewes Caspar, Alexander Tessa, Büttner Benedikt, Hinz José, Alpert Ayelet, Popov Aron-F, Beißbarth Tim, Tzvetkov Mladen, Grade Marian, Quintel Michael, Bergmann Ingo, Mansur Ashham
Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany.
Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
J Clin Med. 2021 Nov 15;10(22):5302. doi: 10.3390/jcm10225302.
(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan-Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary.
（1）背景：脓毒症是主要的死亡原因，也是一个全球公共卫生问题。因此，解读该疾病的潜在分子机制及其发病率和死亡率的决定因素至关重要。本研究检测了负性共刺激淋巴细胞激活基因3（LAG-3）的rs951818单核苷酸多态性（SNP）对脓毒症死亡率和疾病严重程度的影响。（2）方法：从哥廷根大学医学中心的三个外科重症监护病房前瞻性纳入707例连续的脓毒症患者。将28天和90天死亡率作为主要结局进行分析，而疾病严重程度参数作为次要终点。（3）结果：在Kaplan-Meier分析中，LAG-3 rs951818 AA纯合子患者的28天死亡率（17.3%）显著低于C等位基因携带者（23.7%，P = 0.0476）。此外，这些患者在病程中接受有创机械通气的比例（96%）高于C等位基因携带者（92%，P = 0.0466）。（4）结论：单独或与其他遗传生物标志物联合对LAG-3基因变异进行基因分型，可能是脓毒症患者风险分层的一种有前景的方法。针对免疫检查点（如LAG-3）进行患者个体化治疗靶向，可能是未来脓毒症治疗的一个组成部分。有必要在临床相关的脓毒症模型中进行进一步详细研究。
