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  • The hypothalamic pituitary adrenal HPA axis is

    2023-11-20

    The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that is central to regulating responses to stress (Palazidou, 2012). GYKI 52466 dihydrochloride In older persons, a high dysfunction of the HPA axis is observed (Otte et al., 2005) which may be enhanced by stimulatory effects of genes involved in the axis, such as that coding for the angiotensin converting enzyme (ACE). ACE converts Angiotensin I into Angiotensin II to regulate cardiovascular homeostasis (Sayed-Tabatabaei et al., 2006). ACE also has a well-characterised role in regulating the HPA axis following stress-activation through stimulatory effects on two hormones, adrenocorticotropin hormone (ACTH) and corticotropin-releasing-hormone (CRH)(Armando et al., 2007, Pavlatou et al., 2008). Hyperactivity of the axis is observed consistently in depressed patients, as attested by elevated levels of cortisol, CRH and ACTH (Lloyd and Nemeroff, 2011). ACE is notably considered a candidate susceptibility factor for the bi-directional relationship between depression and CVD (Bondy, 2007). Genetic studies have linked several ACE genetic variants to an increased risk of depression (Baghai et al., 2006, Lopez-Leon et al., 2008, Ancelin et al., 2013) and to antidepressant treatment response (Baghai et al., 2001, Baghai et al., 2004). ACE polymorphisms have also been shown to regulate GYKI 52466 dihydrochloride secretion, a measure of HPA axis activity (Baghai et al., 2002, Baghai et al., 2006, Ancelin et al., 2013). To date, few studies have investigated DNA methylation of ACE and its association with depression. This study used data gathered from a large population based cohort of older individuals to investigate the associations between depression status and methylation at the promoter region of the ACE gene in peripheral blood. Analyses were adjusted for participants’ lifestyle, health and medical history. Potential modifying effects of genetic variation across the ACE gene and cortisol levels were also considered.
    Methods
    Results
    Discussion No significant association between depression status and ACE promoter methylation in isolation was found in this older population of 552 individuals after adjustment for a wide range of potential confounding factors. However, there was evidence that ACE genetic variants were associated with methylation, and modified the association between depression and methylation. In particular, depression was associated with significantly decreased ACE methylation at CpG 28.29.30 for four variants, and significantly increased ACE methylation at CpGs 1, 14 and 17 for three variants. These novel findings were not confounded by sex, age, antidepressant use or other factors examined, including vascular disorder. Furthermore, in a small sub-sample, we provide some preliminary support that lower ACE methylation was correlated with higher cortisol levels, independent of depression status. Previous studies have suggested the ACE gene to be implicated in depression onset (Baghai et al., 2006, Lopez-Leon et al., 2008, Ancelin et al., 2013), antidepressant response (Baghai et al., 2001, Baghai et al., 2004) and cortisol signaling (Baghai et al., 2002, Baghai et al., 2006, Ancelin et al., 2013). However, only one prior study has investigated ACE promoter methylation in the context of depression (Zill et al., 2012). In a case-control study, Zill et al. (2012) analysed methylation in peripheral white blood cells, targeting a similar region of the ACE promoter to that examined in our study. In contrast to our findings however, they reported an overall pattern of hypermethylation of the ACE promoter in 81 MDD-diagnosed individuals compared to 81 non-depressed adults. They observed significant associations at 3 of 24 CpG sites examined, corresponding to CpG 14, 19–23 and 24.25 in our study. We also observed hypermethylation at CpG 14 in depressed participants, however with specific genotypes (see below). It should be noted that CpG 19–23 and 24.25 were not included in any of our analyses (failing initial quality control-see Methods) and CpG 28.29.30 was not examined in their study. Additionally, the average methylation levels at each CpG in our study appeared to be consistently lower (ranging from to 9%) than that observed by Zill et al. (2012) (up to 16%).