The initial finding was from an epigenome-wide association study (EWAS) on anxiety in the cross-sectional, population-based KORA F4 study of 1,522 adults (age 32-72 years) recruited from the city of Augsburg and the two adjacent counties in the south of Germany who were administered the Generalized Anxiety Disorder instrument. Whole blood DNA methylation and circulating levels of inflammatory markers (hs-CRP and IL-18) were measured and compared in individuals with or without anxiety. Anxiety associated with an increase of almost 50% of CpG methylation in the promoter of Asb1, a gene located on chromosome 2q37, which encodes a protein with 335 amino acids. The ASB1 protein is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins and is expressed in a number of tissues, including blood cells and brain. This protein has been shown to be involved in both the nervous and immune systems. The work was conducted by Dr. Rebecca Emeny and colleagues as part of the Mental Health working group headed by Prof. Karl-Heinz Ladwig, Institute of Epidemiology II (EPI II) at the Helmholtz Zentrum München (HMGU).
The population-based results suggested epigenetic regulation of the stress-responsive Asb1 gene in severe anxiety which was then validated in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). These findings in humans were then reverse-translated in a mouse model of acute social defeat stress by the MPIP collaborators led by Dr. Elisabeth Binder.
While future studies need to mechanistically dissect the functional relationship between Asb1 methylation and expression and inflammatory consequences in the context of both acute and chronic anxiety, these studies suggest that the altered regulation of Asb1 in response to acute stress is specific for peripheral blood and may be relevant for changes in levels of peripheral inflammation. This adds to the mounting evidence of immunologically distinct mechanisms that may underlie pathogenesis of stress-related disorders and contributes to the aim of the Helmholtz Zentrum München to develop new approaches for the diagnosis, therapy and prevention of these most common mental health diseases.
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