DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression.

The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder

Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. Methods: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. Results: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1β (IL-1β) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. Conclusions: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention

Demographic characteristics of the depressed patients (MD) and healthy controls (CON).

<p>Demographic characteristics of the depressed patients (MD) and healthy controls (CON).</p

ACE serum concentrations (baseline) among the total sample, medication-free depressive patients (MD) and controls (CON) in relation to their methylation status in the (−456/−255) region of the ACE gene.

<p>Methylated probes showed lower ACE concentrations (p = 0.005, F = 8.1). This effect was also obvious in depressive patient (p = 0.03, F = 5.1). In the control group there was a similar pattern, but without statistical significance. *: p<0.05 (ANCOVA). Data are mean values ± s.e.m.</p

Correlation analysis between the inflammatory marker serum concentrations (baseline) and the ACE methylation frequency over all 24 CpG sites of each probe.

<p>We found a significant inverse correlation between the methylation frequency and the serum baseline concentrations of ICAM-1 (r = −0.289, p = 0.02), E-selectin (r = −0.249, p = 0.04) and P-selectin (r = −0.333, p = 0.01); (Pearson’s correlation).</p

Frequency of DNA methylation in the investigated ACE promoter region.

<p>(a) Frequency of DNA methylation at 24 CpG sites, located in the (−456/−255) region of the ACE gene in depressive patients (MD) and healthy controls (CON); *: p<0.05 (χ2-test). (b) Sequence of the (−456/−255) region (italic, underlined) including the 24 investigated CpG sites (bold). (c) Frequency of methylation and non-methylation at the 24 CpG sites, located in the (−456/−255) region of the ACE gene in depressive patients (MD) and healthy controls (CON). Patients have a significantly higher methylation status than the healthy controls (p = 0.008, χ2 = 7.1, df = 1). *: p<0.05 (χ2-test).</p

Frequency of DNA methylation at 24 CpG sites, located in the (−456/−255) region of the ACE gene in human post mortem samples of hippocampus and cortex from 13 control individuals.

<p>Frequency of DNA methylation at 24 CpG sites, located in the (−456/−255) region of the ACE gene in human post mortem samples of hippocampus and cortex from 13 control individuals.</p

Serum concentrations of inflammatory markers (baseline) among medication-free depressive patients in relation to their methylation status in the (−456/−255) region of the ACE gene.

<p>Patients with methylated CpG sites in the (−456/−255) region showed decreased concentrations of all inflammatory markers compared to unmethylated patient samples (not statistically significant).</p