King's College London, Section and Laboratory of Stress, Psychiatry and Immunology, Institute of Psychiatry, London, UK.
Mol Psychiatry. 2009 Dec;14(12):1095-104. doi: 10.1038/mp.2008.48. Epub 2008 May 6.
Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.
抑郁和疲劳是干扰素-α（IFN-α）治疗的常见副作用，有充分的证据表明，炎症反应系统（包括白细胞介素 6，IL-6）和 5-羟色胺能系统在这些症状的病理生理学中起重要作用。已经确定白细胞介素 6 基因（rs1800795）和 5-羟色胺转运体基因（5-HTTLPR）启动子区域的功能性多态性可以调节这些系统。本研究旨在确定这些多态性是否与 IFN-α 和利巴韦林治疗期间抑郁和疲劳的发展有关。98 名接受聚乙二醇化 IFN-α和利巴韦林治疗慢性丙型肝炎病毒的高加索患者在伦敦国王学院医院和亚特兰大埃默里大学医院参与了这项前瞻性队列研究。在治疗前和治疗期间的第 4、8、12 和 24 周测量抑郁和疲劳症状。“低 IL-6”合成基因型（CC）与抑郁症状明显减少有关（第 24 周的效应大小为 0.7；F = 9.4，d.f. = 436，P = 0.002）。“高转录”5-羟色胺转运体（5-HTT）基因型（LL）也与抑郁症状明显减少有关，但效应较小（第 24 周的效应大小为 0.2；F = 4.5，d.f. = 436，P = 0.03）。这两种多态性均与疲劳症状无关（IL-6：F = 1.2，d.f. = 430，P = 0.2；5-HTT：F = 0.5，d.f. = 430，P = 0.5）。5-HTT 多态性对抑郁的较小影响可能是由于基因之间的相互作用（F = 5.0，d.f. = 434，P = 0.02）：5-HTTLPR 多态性的“保护”作用仅在存在“低 IL-6”基因型时才明显（F = 5.4，d.f. = 64，P = 0.02），而不是在存在“高 IL-6”基因型时明显（F = 2.2，d.f. = 369，P = 0.1）。白细胞介素 6 多态性与抑郁症状风险降低之间的关联证实了炎症反应系统在 IFN-α 诱导的抑郁病理生理学中的作用；相比之下，5-HTT 基因的作用较小，可能取决于炎症反应的状态。
