Genetic variations of ionotropic glutamate receptor pathways on interferon-α-induced depression in patients with hepatitis C viral infection

Importance: The most supportive evidence of the inflammation theory of depression is that up to one-third of patients with Hepatitis C virus infection (HCV) develop clinical depressive episodes during interferon-α (IFN-α) therapy. As glutamate-mediated excitotoxicity has been found to be a consequence of excessive inflammation and a pathogenic mechanism of depression, it is plausible to investigate genes on ionotropic glutamate receptor pathways. Objective: To identify the at-risk genetic variations on ionotropic glutamate receptor pathways for interferon-α-induced depression. Method: We assessed 291 patients with chronic HCV undergoing IFN-α therapy and analyzed the single nucleotide polymorphisms (SNPs) in genes related to ionotropic glutamate receptors in this prospective case-control study. Patients who developed IFN-α-induced depression anytime during the treatment were defined as the case group, while those who did not were defined as the control group. Genomic DNA was extracted from peripheral blood and analyzed by Affymetrix TWB array. Allelic and haplotype association tests were conducted using χ2 tests to assess the difference in allele and haplotype frequencies between cases and controls. Additionally, we performed 5000 permutations to control gene-wide family-wise error rates and create empirical p-values. Results: The minor and major allele frequencies of rs7542 (empirical p-value = 0.0310) in MAPK3, rs3026685 (empirical p-value = 0.0378) in PICK1, rs56005409 (empirical p-value = 0.0332) in PRKCA, rs12914792 (empirical p-value = 0.0096), rs17245773 (empirical p-value = 0.0340) in RASGRF1, and rs78387863 (empirical p-value = 0.0086), rs74365480 (empirical p-value = 0.0200) in RASGRF2 were found significantly different between cases and controls. Haplotype association tests also revealed one significant haplotype in PRKCA (empirical p-value = 0.0200) and one in RASGRF1 (empirical p-value = 0.0048). Conclusions: This study provided supportive evidence of the involvement of the RAS/RAF/mitogen-activated protein kinase (MAPK) signaling pathway and glutamate ionotropic receptor AMPA type subunit 2(GluR2) transportation in the pathogenesis of IFN-α-induced depression.