Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment

• Type of Material: Article
• Authors: S.J. Bull, King’s College London; P. Huezo-Diaz, King’s College London; Elisabeth Binder, Emory University; Joseph Cubells, Emory University; G. Ranjith, King’s College London; C. Maddock, King’s College London; C. Miyazaki, King’s College London; N. Alexander, Emory University; M. Hotopf, King’s College London; A.J. Cleare, King’s College London; S. Norris, St. James's Hospital; E. Cassidy, Cork University Hospital; K.J. Aitchison, King’s College London; Andrew Miller, Emory University; Carmine Pariante, Emory University
• Language: English
• Date: 2009-12-01
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Nature Publishing Group All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/mp.2008.48
• Title of Journal or Parent Work: MOLECULAR PSYCHIATRY
• Volume: 14
• Issue: 12
• Start Page: 1095
• End Page: 1104
• Grant/Funding Information: The USA arm of the study was funded by grant numbers K05 MH069124 and R01 MH60723 (National Institute of Mental Health), a NARSAD Independent Investigator Award to J Cubells, and by support from the Schering-Plough corporation.; Dr CM Pariante and the UK arm of this study were funded by grants from the Guy’s and St Thomas’ Charitable Foundation, the NIHR Specialist Biomedical Research Centre for Mental Health at South London and Maudsley NHS Trust and Institute of Psychiatry (Kings’ College London), the UK Medical Research Council and the NARSAD.
• Keywords: CANCER-PATIENTS; Life Sciences & Biomedicine; VIRAL CLEARANCE; PROMOTER POLYMORPHISM; Neurosciences; fatigue; CHRONIC HEPATITIS-C; Science & Technology; TRYPTOPHAN DEPLETION; immunotherapy; Biochemistry & Molecular Biology; Neurosciences & Neurology; MAJOR DEPRESSION; ASSOCIATION; serotonin transporter; interleukin-6; PLUS RIBAVIRIN; depressive symptoms; Psychiatry; cytokine; IMMUNE ACTIVATION; SICKNESS BEHAVIOR
• Research Categories: Psychology, Physiological; Biology, Neuroscience; Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Depression and fatigue are frequent side effects of interferon-α (IFN-α) 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-α and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-α 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 size0.7 at week 24; F9.4, 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 size0.2 at week 24; F4.5, d.f.436, P=0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F1.2, d.f.430, P=0.2; 5-HTT: F0.5, 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 (F5.0, 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 (F5.4, d.f.64, P=0.02), not in the presence of the high IL-6 genotype (F2.2, 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-α-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.