Cheng Szu-Wei, Li Jing-Xing, Chen Daniel Tzu-Li, Chien Yu-Chuan, Chang Jane Pei-Chen, Huang Shih-Yi, Galecki Piotr, Su Kuan-Pin
College of Medicine, China Medical University, Taichung 404, Taiwan.
Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung 404, Taiwan.
J Pers Med. 2021 Mar 11;11(3):192. doi: 10.3390/jpm11030192.
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. 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. With sex and education level as covariates, rs8082252 ( = 0.0015, odds ratio = 2.716), rs8082142 ( 0.0031, odds ratio = 2.499) in arylformamidase (, and rs12477181 ( 0.0004, odds ratio = 0.3478) in kynureninase ( were significant in logistic regression models with dominant modes of inheritance. Haplotype analyses showed the two significant SNPs in to be in the same haploblock and highly correlated (r = 0.99). There were two significant haplotypes (by the sequence of rs8082252, rs8082142): AT (χ2 = 7.734, 0.0054) and GC (χ2 = 6.874, 0.0087). 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.
在干扰素-α（IFN-α）治疗期间，重度抑郁发作的高发生率被认为是抑郁症炎症理论最有力的支持证据。由于犬尿氨酸途径在连接炎症和抑郁方面起着重要作用，因此研究该途径中用于预测IFN-α诱导抑郁症的遗传标记是合理的。在这项前瞻性病例对照研究中，我们评估了291例接受IFN-α治疗的慢性丙型肝炎病毒感染患者，并分析了犬尿氨酸途径中基因的单核苷酸多态性（SNP）。我们的病例组包括在治疗期间发生IFN-α诱导抑郁症的患者，其他患者被定义为对照组。从外周血白细胞中提取基因组DNA，并通过Affymetrix TWB阵列进行分析。我们首先使用Fisher精确检验对每个SNP测试等位基因、显性和隐性模型。然后，我们基于每个SNP的最佳模型进行5000次全基因范围的最大（T）排列，以提供强大的全基因家族错误率控制。最后，我们对先前程序中获得的显著SNP进行逻辑回归分析，将性别和教育水平作为协变量来构建预测模型。使用Haploview 4.2进行额外的单倍型分析，以研究基因内多个显著SNP的联合效应。以性别和教育水平作为协变量，芳基甲酰胺酶中的rs8082252（P = 0.0015，比值比 = 2.716）、rs8082142（P = 0.0031，比值比 = 2.499）以及犬尿氨酸酶中的rs12477181（P = 0.0004，比值比 = 0.3478）在具有显性遗传模式的逻辑回归模型中具有显著性。单倍型分析表明，芳基甲酰胺酶中的两个显著SNP位于同一单倍型块中且高度相关（r = 0.99）。有两个显著的单倍型（按rs8082252、rs8082142的顺序）：AT（χ2 = 7.734，P = 0.0054）和GC（χ2 = 6.874，P = 0.0087）。本研究为犬尿氨酸途径参与IFN-α诱导的抑郁症提供了支持证据。该途径中的SNP也可预测这种疾病。
