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Association of a polymorphism in the indoleamine- 2,3-dioxygenase gene and interferon-α-induced depression in patients with chronic hepatitis C

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 two 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. Before 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 (confidence interval: 1.48–5.73) compared with 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 IDO has an important role in cytokine-induced behavioral changes.

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Acknowledgements

This study was supported by a grant from Schering-Plough Research Institute as well as a Mentored Scientist Development Award from the National Institutes of Health to JC (K01DA015766). Alicia K Smith has received research support from Schering-Plough Research Institute; Jason S Simon is an employee of Eisai Incorporated; Eric L Gustaffson, David J Devlin, Ping Qiu, Janice K Albrecht and Clifford A Brass are employees of Merck Research Laboratories and are stockholders in this company; Stephanie Noviello is a consultant for Merck Research Laboratories; Joseph F Cubells has served as a consultant for Barnes and Thornberg, LLP and has received research support from Seaside Therapeutics and Schering-Plough Research Institute; Mark S Sulkowski has served on the advisory board and received research support from Abbott Laboratories, Bristol Meyers Squibb, Boehringer Ingelheim Pharmaceuticals, F Hoffmann-La Roche, Gilead Sciences Incorporated, Merck Research Laboratories, Tibotec and Vertex Pharmaceuticals, has served on the advisory board of GlaxoSmithKline, has been a consultant for Biolex Therapeutics and Teva Pharmaceutical Industries and served on a study steering committee for Pfizer; John G McHutchinson is an employee of Gilead Sciences Incorporated; Andrew H Miller has served as a consultant for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Lunbeck Research USA, F Hoffmann-La Roche, Schering-Plough Research Institute and Wyeth/Pfizer and has received research support from Centocor, GlaxoSmithKline and Schering-Plough Research Institute.

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Smith, A., Simon, J., Gustafson, E. et al. Association of a polymorphism in the indoleamine- 2,3-dioxygenase gene and interferon-α-induced depression in patients with chronic hepatitis C. Mol Psychiatry 17, 781–789 (2012). https://doi.org/10.1038/mp.2011.67

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