Szu-Wei Cheng1, Jing-Xing Li1, Yu-Chuan Chien2, Jane Pei-Chen Chang3, Sergey Shityakov4, Shih-Yi Huang5, Piotr Galecki6, Kuan-Pin Su7. 1. College of Medicine, China Medical University, Taichung, Taiwan. 2. Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. 3. College of Medicine, China Medical University, Taichung, Taiwan; Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 4. College of Medicine, China Medical University, Taichung, Taiwan; Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; Department of Bioinformatics, Würzburg University, Würzburg, Germany. 5. School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan. 6. Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland. 7. College of Medicine, China Medical University, Taichung, Taiwan; Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; An-Nan Hospital, China Medical University, Tainan, Taiwan. Electronic address: cobolsu@gmail.com.
Abstract
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. Stratified analyses were then done to control for confounders and adjust odds ratios for our significant SNPs. We also did an additional stratified analysis to re-assess genes with near-significant SNPs (empirical p-value=0.05-0.10), employing Bonferroni correction with the effective number of independent tests to control gene-wide family-wise error rates. 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). Stratified analyses showed no signs of confounders for most of our significant SNPs, except for rs78387863 in RASGRF2. After a re-assessment of our near-significant genes by stratified analyses, two SNPs in GRIN2B turned significant. 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.
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. Stratified analyses were then done to control for confounders and adjust odds ratios for our significant SNPs. We also did an additional stratified analysis to re-assess genes with near-significant SNPs (empirical p-value=0.05-0.10), employing Bonferroni correction with the effective number of independent tests to control gene-wide family-wise error rates. 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). Stratified analyses showed no signs of confounders for most of our significant SNPs, except for rs78387863 in RASGRF2. After a re-assessment of our near-significant genes by stratified analyses, two SNPs in GRIN2B turned significant. 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.
Authors: Szu-Wei Cheng; Jing-Xing Li; Daniel Tzu-Li Chen; Yu-Chuan Chien; Jane Pei-Chen Chang; Shih-Yi Huang; Piotr Galecki; Kuan-Pin Su Journal: J Pers Med Date: 2021-03-11