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.

中文翻译：

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丙型肝炎病毒感染患者干扰素-α诱导的抑郁症的离子型谷氨酸受体通路的遗传变异

重要性 抑郁症炎症理论最支持的证据是，多达三分之一的丙型肝炎病毒感染 (HCV) 患者在干扰素-α (IFN-α) 治疗期间会出现临床抑郁发作。由于已发现谷氨酸介导的兴奋性毒性是过度炎症的结果和抑郁症的致病机制，因此研究离子型谷氨酸受体通路上的基因是合理的。目的 确定干扰素-α 诱导的抑郁症的离子型谷氨酸受体通路的高危遗传变异。方法 我们评估了 291 名接受 IFN-α 治疗的慢性 HCV 患者，并在这项前瞻性病例对照研究中分析了与离子型谷氨酸受体相关基因的单核苷酸多态性 (SNP)。在治疗期间任何时候出现 IFN-α 诱导的抑郁症的患者定义为病例组，而未出现的患者定义为对照组。从外周血中提取基因组 DNA 并通过 Affymetrix TWB 阵列进行分析。使用 χ2 检验进行等位基因和单倍型关联测试，以评估病例和对照之间等位基因和单倍型频率的差异。此外，我们进行了 5000 次排列以控制全基因家族的错误率并创建经验 p 值。结果 MAPK3 中 rs7542（经验 p 值=0.0310）的次要和主要等位基因频率，PICK1 中的 rs3026685（经验 p 值=0.0378），PRK9 中 rs56005409（经验 p 值 = 0.0332）的等位基因频率 (p-值=0.0096)、RASGRF1 中的 rs17245773（经验 p 值=0.0340）和 rs78387863（经验 p 值=0.0086），发现 RASGRF2 中的 rs74365480（经验 p 值 = 0.0200）在病例和对照之间有显着差异。单倍型关联测试还揭示了 PRKCA 中的一种显着单倍型（经验 p 值 = 0.0200）和 RASGRF1 中的一种（经验 p 值 = 0.0048）。结论 本研究提供了 RAS/RAF/丝裂原活化蛋白激酶 (MAPK) 信号通路和谷氨酸离子型受体 AMPA 型亚基 2 (GluR2) 转运参与 IFN-α 诱导的抑郁症发病机制的支持性证据。