Abstract
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 β4 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.
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Acknowledgements
This study was supported by NIH grants GM61394, RR017365, MH062777, RR000865, RR16996, HG002500 and DK063240, and institutional funds from the University of Miami, Department of Psychiatry & Behavioral Sciences. We thank the Mexican American individuals who have participated in this study. We are grateful for the contributions to the care of our patients from Dr Israel Alvarado, Dr Deborah Flores and Dr Anil Sharma; our nursing staff Rita Jepson and Lorraine Garcia-Teague; our social workers Patricia Reyes and Gabriela Marquez at the Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA) and staff of the UCLA GCRC. We thank Dr Kristopher Irizarry (UCLA), Dr Luciana Ribeiro (University of Miami) and Dr Joao Busnello (University of Miami) who have helped us with bioinformatics and database aspects of the work. We are also grateful for the contributions of Fiona O’Kirwan and Sarika Thakur (Semel Institute), and Dr Rita Cantor, Department of Genetics, UCLA, in preliminary statistics analyses. We also thank Dr Scott Weiss for facilitating our interactions with the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, and Dr Panos Deloukas for facilitating genotyping work at the Wellcome Trust Sanger Institute, UK.
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Wong, ML., Dong, C., Maestre-Mesa, J. et al. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13, 800–812 (2008). https://doi.org/10.1038/mp.2008.59
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DOI: https://doi.org/10.1038/mp.2008.59
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