Wong M-L, Dong C, Maestre-Mesa J, Licinio J
Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Mol Psychiatry. 2008 Aug;13(8):800-12. doi: 10.1038/mp.2008.59. Epub 2008 May 27.
There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome beta4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups.
重度抑郁症（MDD）的抑郁症状的性质和病程与炎症性疾病的抑郁症状之间存在临床相似之处。然而，确定MDD中可能存在的免疫系统失调一直具有挑战性。新出现的数据支持T细胞功能障碍的作用。在此，我们报告了MDD以及墨西哥裔重度抑郁症患者对抗抑郁药的反应与在调节下丘脑-垂体-肾上腺轴和免疫功能中起重要作用的基因之间的关联。具体而言，对T细胞功能至关重要的两个基因中的单核苷酸多态性（SNP）与MDD易感性相关：对抗原加工很重要的蛋白酶体β4亚基（PSMB4）和对分化至关重要的T盒21（TBX21，T-bet）。我们的分析揭示了显著的联合等位基因剂量效应：携带一个、两个和三个风险等位基因的个体被诊断为MDD的可能性分别是常人的2.3倍、3.2倍和9.8倍。我们发现了几个SNP与抗抑郁药反应之间的关联；这些基因支持T细胞（CD3E、PRKCH、PSMD9和STAT3）以及下丘脑-垂体-肾上腺轴（UCN3）功能在治疗反应中的作用。我们还描述了MDD中CXCL10/IP-10水平升高，而抗抑郁药治疗后该水平下降。这进一步表明MDD中1型T细胞活性占主导。我们在此描述的T细胞功能变异可能占中度MDD墨西哥裔美国人可归因风险的47.8%。免疫功能基因具有高度变异性；因此，不同的基因可能在不同的人群中起作用。
