Predictive Genetic Variations in the Kynurenine Pathway for Interferon-α-Induced Depression in Patients with Hepatitis C Viral Infection

Abstract

Importance: The high incidence of major depressive episodes during interferon-α (IFN-α) therapy is considered the most powerful supportive evidence for the inflammation theory of depression. As the kynurenine pathway plays an important role connecting inflammation and depression, it is plausible to investigate this pathway for predictive genetic markers for IFN-α-induced depression. Methods: In this prospective case-control study, we assessed 291 patients with chronic hepatitis C viral infection taking IFN-α therapy and analyzed the single nucleotide polymorphisms (SNPs) in genes in the kynurenine pathway. Our case group contained patients who developed IFN-α-induced depression during the treatment, and others were defined as the control group. Genomic DNA was extracted from leukocytes in the peripheral blood and analyzed by Affymetrix TWB array. We first tested allelic, dominant, and recessive models on each of our SNPs using Fisher’s exact test. We then conducted 5000 gene-wide max(T) permutations based on the best model of each SNP to provide strong gene-wide family-wise error rate control. Finally, we preformed logistic regression for the significant SNPs acquired in previous procedures, with sex and education level as covariates to build predictive models. Additional haplotype analyses were conducted with Haploview 4.2 to investigate the combining effect of multiple significant SNPs within a gene. Results: With sex and education level as covariates, rs8082252 (p = 0.0015, odds ratio = 2.716), rs8082142 (p = 0.0031, odds ratio = 2.499) in arylformamidase (AFMID), and rs12477181 (p = 0.0004, odds ratio = 0.3478) in kynureninase (KYNU) were significant in logistic regression models with dominant modes of inheritance. Haplotype analyses showed the two significant SNPs in AFMID to be in the same haploblock and highly correlated (r2 = 0.99). There were two significant haplotypes (by the sequence of rs8082252, rs8082142): AT (χ2 = 7.734, p = 0.0054) and GC (χ2 = 6.874, p = 0.0087). Conclusions: This study provided supportive evidence of the involvement of the kynurenine pathway in IFN-α-induced depression. SNPs in this pathway were also predictive of this disease.

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan

“…The genome-wide permutations process powered by an accelerated expectation-maximization algorithm [34] or SNPs and haplotypes has been recognized as a valid predictor for the effects of multiple genes and linkage disequilibrium [35,36]. For instance, previous studies provided evidence suggesting the possible pathology of the kynurenine pathway [10] and the ionotropic glutamate receptor pathways [11] in MDD. Furthermore, to evaluate the combination effect of each SNP in the same gene, we carried out the haplotype association tests with Haploview 4.2.…”

“…Genome-wide association studies (GWAS) provide insights for the exploration of potential pathological genes in MDD. For instance, based on GWAS, genes such as Kynureninase (KYNU), Sirtuin (SIRT), glutamate ionotropic receptor AMPA type subunit 2 (GluR2), Neuronal Growth Regulator 1 (NEGR1), and High Mobility Group Box 1 (HMGB1) may relate to depressive symptoms [6][7][8][9][10][11]. Some of these aforementioned genes, including KYNU and SIRT, are also associated with NAD.…”

Different Aspects of Psoriasis : Comorbidity, Comedication and Disease Biomarkers

“…In follow-ups these individuals have shown to be prone to relapse into new depressive episodes ( 101) -hypothetically triggered by major stressful events or major infections. Genetic studies have also suggested that patients that develop depression under IFN-α have higher frequencies of certain genetic variations, single nucleotide polymorphisms (SNPs), associated to glutamate receptor pathways and kynurenine pathways (102,103). This could support the theory that individuals genetically predisposed may react to inflammation with changes in 5-HT levels or glutamate levels in the brain.…”

Neuroimmunology and (Epi)Genetics in Depressive Disorders

“…However, in a situation of increased activation of the immune system, inflammatory factors cause excessive activation of IDO (indoleamine-2,3-dioxygenase), an enzyme present in microglia, astrocytes and neurons, catabolizing the transformation of tryptophan into the neurotoxic kynurenine (KYN), thereby reducing the availability of tryptophan for the production of serotonin. Kynurenine, in turn, influences the intensification of neurodegenerative processes [ 6 ].…”