Association of a Polymorphism in the Indoleamine-2,3-Dioxygenase Gene and Interferon-α-Induced Depression in Patients with Chronic Hepatitis C

• Type of Material: Article
• Authors: Alicia K Smith, Emory University; Jason S. Simon, Schering Plough Research Institute; Eric L. Gustafson, Schering Plough Research Institute; Stephanie Noviello, Schering Plough Research Institute; Joseph F Cubells, Emory University; Michael Epstein, Emory University; David J. Devlin, Schering Plough Research Institute; Ping Qiu, Schering Plough Research Institute; Janice K. Albrecht, Schering Plough Research Institute; Clifford A. Brass, Schering Plough Research Institute; Mark S. Sulkowski, Johns Hopkins University; John G. McHutchinson, Duke University; Andrew H Miller, Emory University
• Language: English
• Date: 2012-07
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Macmillan Publishers Limited. All rights reserved
• Final Published Version (URL): http://www.nature.com/mp/journal/v17/n8/full/mp201167a.html
• Title of Journal or Parent Work: Molecular Psychiatry
• ISSN: 1359-4184
• Volume: 17
• Issue: 8
• Start Page: 781
• End Page: 789
• Grant/Funding Information: This study was supported by a grant from Schering Plough Research Institute as well as a Mentored Scientist Development Award from the National Institute of Health to JC (K01DA015766).
• Keywords: cytokines; genes; indoleamine-2; single nucleotide polymorphism; interferon-α; 3-dioxygenase; depression
• Research Categories: Biology, Genetics; Psychology, General

Abstract

Interferon (IFN)-α treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in IFN-α-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-α-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-α-induced depression were explored in 2 self-reported ethnic groups, Caucasians (n=800) and African Americans (n=232), participating in a clinical trial on the impact of three pegylated IFN-α treatment regimens on sustained viral response in patients with chronic hepatitis C. Prior to treatment, all subjects were free of psychotropic medications and had a score ≤20 on the Center for Epidemiologic Studies Depression Scale (CES-D), which was used to assess depressive symptom severity throughout the study. In Caucasians, a polymorphism (rs9657182) in the promoter region of the gene encoding indoleamine-2,3-dioxygenase (IDO1) was found to be associated with moderate or severe IFN-α-induced depressive symptoms (CES-D >20) at 12 weeks of IFN-α treatment (p=0.0012, p<0.05 corrected). Similar results were obtained for treatment weeks 24, 36 and 48. In subjects homozygous for the risk allele (CC, n=150), the odds ratio for developing moderate or severe depressive symptoms at treatment week 12 was 2.91 (CI: 1.48–5.73) compared to TT homozygotes (n=270). rs9657182 did not predict depression in African Americans, who exhibited a markedly lower frequency of the risk allele at this locus. The findings in Caucasians further support the notion that indoleamine-2,3-dioxygenase plays an important role in cytokine-induced behavioral changes.