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

Interferon (IFN)-alpha treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in IFN-alpha-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-alpha-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-alpha-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-alpha 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-alpha-induced depressive symptoms (CES-D > 20) at 12 weeks of IFN-alpha 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. Molecular Psychiatry (2012) 17, 781-789; doi:10.1038/mp.2011.67; published online 21 June 2011