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Author Notes:

Corresponding Author: Andrew H. Miller, M.D.; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road, Fifth Floor, Atlanta, GA 30322; Phone (404) 712-8800, FAX (404) 727-3233; amill02@emory.edu

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Research Funding:

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:

  • interferon-α
  • indoleamine-2
  • 3-dioxygenase
  • cytokines
  • depression
  • genes
  • single nucleotide polymorphism

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

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Journal Title:

Molecular Psychiatry

Volume:

Volume 17, Number 8

Publisher:

, Pages 781-789

Type of Work:

Article | Post-print: After Peer Review

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.

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