细胞因子和血管内皮生长因子相关基因的全基因组关联研究：低剂量氯胺酮输注治疗难治性抑郁症。
Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression.
机构信息
Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Shih-Pai Road, Sec. 2, 11217, Taipei, Taiwan.
Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
出版信息
CNS Drugs. 2023 Mar;37(3):243-253. doi: 10.1007/s40263-023-00989-7. Epub 2023 Feb 10.
BACKGROUND AND OBJECTIVE
Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression.
METHODS
Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion.
RESULTS
Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5 mg/kg and 0.2 mg/kg) ketamine.
CONCLUSIONS
Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine.
CLINICAL TRIAL REGISTRATION
University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985.
背景与目的
氯胺酮可能具有抗炎作用，并且可增加治疗抵抗性抑郁症患者血管内皮生长因子（VEGF）的水平。但是，与促炎和抗炎细胞因子及 VEGF 相关的基因是否可以预测氯胺酮治疗的反应尚不清楚。因此，本研究的目的是分析与治疗抵抗性抑郁症患者接受低剂量氯胺酮治疗反应相关的特定炎症过程和 VEGF 相关基因。
方法
基于我们临床试验的基因组数据，本研究对不同时点抑郁症状的候选基因进行了二次分析。共有 65 例治疗抵抗性抑郁症患者（氯胺酮 0.5mg/kg 组 21 例，氯胺酮 0.2mg/kg 组 20 例，生理盐水组 24 例）接受了 684616 个单核苷酸多态性的基因分型。选择与 80 种细胞因子（白细胞介素[IL]-1、IL-6、肿瘤坏死因子-α和脂联素）和 VEGF（VEGF 和 VEGF 受体）相关的基因进行基于基因的全基因组关联研究，以评估氯胺酮输注的抗抑郁作用。
结果
特定的单核苷酸多态性，包括 IL1R1 中的 rs2540315 和 rs75746675 以及 VEGFC 中的 rs79568085，与氯胺酮输注的快速（240min 内）抗抑郁作用相关；特定的单核苷酸多态性，如 PIGF 中的 Affx-20131665 以及 TNFRSF8 中的 rs8179353、rs8179353 和 rs8179353，与低剂量（联合 0.5mg/kg 和 0.2mg/kg）氯胺酮的持续（长达 2 周）抗抑郁作用相关。
结论
我们的研究结果进一步表明，与抗炎和促炎细胞因子（即 IL-1、IL-2、IL-6、肿瘤坏死因子-α、C 反应蛋白和脂联素）和 VEGF-FLK 信号相关的基因可预测治疗抵抗性抑郁症患者对氯胺酮输注的反应。炎症和 VEGF 系统的协同调节可能有助于氯胺酮的抗抑郁作用。
临床试验注册
日本大学医院医疗信息网临床试验注册（UMIN-CTR）编号：UMIN000016985。
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