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

• 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
• Journal Title: MOLECULAR PSYCHIATRY
• Volume: Volume 14, Number 12
• Publisher: NATURE PUBLISHING GROUP | 2009-12-01, Pages 1095-1104
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/mp.2008.48
• Subjects: Chemistry, Biochemistry; Biology, Neuroscience; Health Sciences, Oncology; Psychology, Physiological
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Neurosciences; Psychiatry; Neurosciences & Neurology; interleukin-6; serotonin transporter; depressive symptoms; fatigue; cytokine; immunotherapy; CHRONIC HEPATITIS-C; VIRAL CLEARANCE; PROMOTER POLYMORPHISM; TRYPTOPHAN DEPLETION; IMMUNE ACTIVATION; SICKNESS BEHAVIOR; MAJOR DEPRESSION; CANCER-PATIENTS; PLUS RIBAVIRIN; ASSOCIATION

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.