title: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Smith
authors.forename: J S
authors.initials: JS
authors.lastname: Simon
authors.forename: E L
authors.initials: EL
authors.lastname: Gustafson
authors.forename: S
authors.initials: S
authors.lastname: Noviello
authors.forename: J F
authors.initials: JF
authors.lastname: Cubells
authors.forename: M P
authors.initials: MP
authors.lastname: Epstein
authors.forename: D J
authors.initials: DJ
authors.lastname: Devlin
authors.forename: P
authors.initials: P
authors.lastname: Qiu
authors.forename: J K
authors.initials: JK
authors.lastname: Albrecht
authors.forename: C A
authors.initials: CA
authors.lastname: Brass
authors.forename: M S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: J G
authors.initials: JG
authors.lastname: McHutchinson
authors.forename: A H
authors.initials: AH
authors.lastname: Miller
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics / Q000523:psychology; D000483:Alleles; D000998:Antiviral Agents / Q000009:adverse effects; D003863:Depression / Q000150:complications / Q000235:genetics* / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000523:psychology*; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000523:psychology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000523:psychology; D011994:Recombinant Proteins / Q000009:adverse effects; D044465:White People / Q000235:genetics / Q000523:psychology
chemical_list: D000998:Antiviral Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a