The Association of HHV-6 and the TNF-α (-308G/A) Promotor with Major Depressive Disorder Patients and Healthy Controls in Thailand

Abstract

Major depressive disorder (MDD) is a silent global health problem that can lead to suicide. MDD development is suggested to result from numerous risk factors, including genetic factors. A precise tool for MDD diagnosis is currently not available. Recently, inflammatory processes have been identified as being strongly involved in MDD development and the reactivation of human herpesvirus type 6 (HHV-6), upregulating cytokines such as TNF-α, which are associated with MDD. Therefore, this study aimed to determine the association of HHV-6 with genetic factors, especially TNF-α mutation, in MDD patients and their relatives compared to healthy controls. The Patient Health Questionnaire (PHQ-9) was used to evaluate MDD status, and 471 oral buccal samples were investigated for HHV-6 infection and viral copy number by qPCR. TNF-α (-308G/A) gene mutation and the cytokines TNF-α, IL-6, and IL-10 were analyzed by high-resolution melting (HRM) analysis and enzyme-linked immunosorbent assay (ELISA). Whole-exome sequencing of buccal samples was performed to analyze for genetic factors. The results showed significantly higher HHV-6 positivities and viral loads in MDD patients (15/59 (25.67%) and 14,473 ± 16,948 copies/µL DNA) and their relatives (blood relatives 17/36 (47.22%) and 8146 ± 5656 copies/µL DNA); non-blood relatives 7/16 (43.75%) and 20,721 ± 12,458 copies/µL DNA) compared to the healthy population (51/360 (14.17%) and 6303 ± 5791 copies/µL DNA). The TNF-α (-308G/A) mutation showed no significant difference. Surprisingly, 12/26 (46.15%) participants with the TNF-α (-308G/A) mutation showed HHV-6 positivities at higher rates than those with wild-type TNF-α (-308G) (70/267 (26.22%)). HHV-6-positive participants with TNF-α (-308G/A) showed higher levels of TNF-α, IL-6, and IL-10 than those of negative control. Exome analysis revealed that common mutations in immune genes were associated with depression. Therefore, this study unveiled the novel association of inflammatory gene TNF-α (-308G/A) mutations with HHV-6 reactivation, which could represent a combined risk factor for MDD. This result could induce further research on MDD development and clinical applications.

Identification of a strong genetic risk factor for major depressive disorder in the human virome

“…In addition, subjects were patients in whom MDD activity was suppressed to a degree because they were under treatment. Also, elevation of blood IL-6 38 previously observed in MDD was not apparent in the MDD patients in the present study due to treatment with antidepressants.…”

“…For the MDD patients and NCs with success in direct sequencing, while there were no significant differences in terms of age, gender ratio, BMI and salivary HHV-6B DNA levels, the antibody titer against SITH-1, was significantly higher in MDD patients ( Table 1 ). Possible reasons that the enhanced reactivation of HHV-6B 38 reported in MDD patients was not observed were the small size of the study population and the intermittent nature of viral reactivation. In addition, subjects were patients in whom MDD activity was suppressed to a degree because they were under treatment.…”

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement

“…Regionally confined HHV-6 reactivation can cause immune dysfunction, neuroinflammation, neurodegeneration, major depressive disorder, and ME/CFS [ 189 , 190 , 191 , 192 , 193 ], potentially accounting for many localized LC phenomena. However, assessing the impact of HHV-6 on systemic low-grade inflammation processes may still be premature.…”