Mewes Caspar, Büttner Benedikt, Hinz José, Alpert Ayelet, Popov Aron-Frederik, Ghadimi Michael, Beissbarth Tim, Tzvetkov Mladen, Jensen Ole, Runzheimer Julius, Quintel Michael, Shen-Orr Shai, Bergmann Ingo, Mansur Ashham
Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany.
Department of Anesthesiology and Intensive Care Medicine, Klinikum Region Hannover, D-30459 Hannover, Germany.
J Clin Med. 2019 Jan 10;8(1):70. doi: 10.3390/jcm8010070.
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a coinhibitory checkpoint protein expressed on the surface of T cells. A recent study by our working group revealed that the rs231775 single nucleotide polymorphism (SNP) in the CTLA-4 gene was associated with the survival of patients with sepsis and served as an independent prognostic variable. To further investigate the impact of CTLA-4 genetic variants on sepsis survival, we examined the effect of two functional SNPs, CTLA-4 rs733618 and CTLA-4 rs3087243, and inferred haplotypes, on the survival of 644 prospectively enrolled septic patients. Kaplan⁻Meier survival analysis revealed significantly lower 90-day mortality for rs3087243 G allele carriers ( = 502) than for AA-homozygous ( = 142) patients (27.3% vs. 40.8%, = 0.0024). Likewise, lower 90-day mortality was observed for TAA haplotype-negative patients ( = 197; compound rs733618 T/rs231775 A/rs3087243 A) than for patients carrying the TAA haplotype ( = 447; 24.4% vs. 32.9%, = 0.0265). Carrying the rs3087243 G allele hazard ratio (HR): 0.667; 95% confidence interval (CI): 0.489⁻0.909; = 0.0103) or not carrying the TAA haplotype (HR: 0.685; 95% CI: 0.491⁻0.956; = 0.0262) remained significant covariates for 90-day survival in the multivariate Cox regression analysis and thus served as independent prognostic variables. In conclusion, our findings underscore the significance of CTLA-4 genetic variants as predictors of survival of patients with sepsis.
细胞毒性T淋巴细胞相关蛋白4（CTLA-4）是一种在T细胞表面表达的共抑制性检查点蛋白。我们工作组最近的一项研究表明，CTLA-4基因中的rs231775单核苷酸多态性（SNP）与脓毒症患者的生存率相关，并作为一个独立的预后变量。为了进一步研究CTLA-4基因变异对脓毒症生存的影响，我们检测了两个功能性SNP，即CTLA-4 rs733618和CTLA-4 rs3087243以及推断单倍型对644例前瞻性纳入的脓毒症患者生存的影响。Kaplan-Meier生存分析显示，rs3087243 G等位基因携带者（n = 502）的90天死亡率显著低于AA纯合子患者（n = 142）（27.3%对40.8%，P = 0.0024）。同样，TAA单倍型阴性患者（n = 197；复合rs733618 T/rs231775 A/rs3087243 A）的90天死亡率低于携带TAA单倍型的患者（n = 447；24.4%对32.9%，P = 0.0265）。在多变量Cox回归分析中，携带rs3087243 G等位基因（风险比[HR]：0.667；95%置信区间[CI]：0.489至0.909；P = 0.0103）或不携带TAA单倍型（HR：0.685；95% CI：0.491至0.956；P = 0.0262）仍然是90天生存的显著协变量，因此作为独立的预后变量。总之，我们的研究结果强调了CTLA-4基因变异作为脓毒症患者生存预测指标的重要性。
