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.

Figure 1. Genomic structure of IDO1 and the position of the polymorphisms examined in relation to linkage disequilibrium in a representative Caucasian sample (CEU)

Linkage disequilibrium in the population is indicated using r² and visualized using haploview.

Figure 2. Development of Moderate or Severe Depression in Caucasians across the 48 week study stratified by TT, CT, and CC genotype at the rs9657182 locus

Depressive symptom severity was assessed across 48 weeks of IFN-α therapy in 800 Caucasian subjects with hepatitis C using the Center for Epidemiologic Studies Depression Scale (CES-D). All subjects were free from psychotropic medications at baseline. Patients homozygous for the C allele (CC) in a polymorphism (rs9657182) in the promoter region of the gene encoding for indoleamine-2,3-dioxygenase (IDO1) exhibited a significantly higher percentage of moderate to severe depression (CES-D >20) compared to those homozygous for the T allele at all time points examined. **p<0.01, *p<0.05 compared to CC genotype.