Epigenome-Wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption Among European American Male Veterans.

BACKGROUND: Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations in DNA methylation. Thus, DNA methylation signatures in peripheral cells may provide biomarkers of the medical impact of alcohol use and the risk for future alcohol consumption. METHOD: Using a high-density methylation array, we characterized epigenome-wide DNA methylation in saliva cells with respect to alcohol consumption in a large cohort of male European American veterans. In this study, DNA methylation of over 870,000 CpG DNA sites was profiled in 1,135 European American men. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Linear regression was applied in an epigenome-wide association study (EWAS), adjusted for confounders. Gene set enrichment analysis was performed in the KEGG database with a correction for gene length. RESULTS: We found that a total of 70 CpG sites reached EWAS-corrected significance (p < 6E-08) with small effects on alcohol consumption for individual CpG sites, including 64 new CpG sites and 6 CpG sites that were previously reported as associated with alcohol use disorder, liver function, body mass index, and lipid metabolism. The most significant CpG site was located in SLC7A11 (t = -11.34, p = 2.66E-28), a gene involved specifically in cysteine and glutamate transportation. The 70 significant CpG sites were located on 44 genes, including genes involved in amino acid transport and metabolism systems. We identified 68 pathways with a false discovery rate < 0.05. CONCLUSIONS: We identified novel DNA methylation sites associated with alcohol consumption. Results may shed light on peripheral mechanisms of alcohol consumption on adverse health outcomes among heavy drinkers.

Alterations in stress reactivity after long-term treatment with paroxetine in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.

Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder.

OBJECTIVE: Previous studies of adults with posttraumatic stress disorder (PTSD) have found various abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis, including enhanced suppression of cortisol following low-dose dexamethasone. The purpose of the present study was to investigate salivary cortisol responses to low-dose dexamethasone in adolescents with PTSD. METHOD: Forty-eight adolescents (20 with current PTSD, 9 trauma controls without PTSD, and 19 healthy nontraumatized controls) were enrolled in the study. On day 1, baseline saliva samples were obtained at 8 a.m. and 0.5 mg of dexamethasone was administered at 11 p.m. Cortisol and dexamethasone levels were assessed at 8 a.m. the following day. RESULTS: Adolescents with current PTSD showed no difference in the suppression of salivary cortisol in response to low-dose (0.5 mg) dexamethasone compared to trauma controls without PTSD and nontraumatized controls. More severely affected PTSD subjects with co-occurring major depression showed higher pre- and post-dexamethasone salivary cortisol levels compared to controls. CONCLUSIONS: The present study did not find evidence for enhanced suppression of salivary cortisol at 8 a.m. following low-dose dexamethasone in multiply traumatized adolescents with PTSD. This result differs from findings in adults with PTSD. Further investigations of hypothalamic-pituitary-adrenal axis abnormalities in traumatized children and adolescents are needed.

Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation, and objective performance in humans exposed to underwater navigation stress.

BACKGROUND: A growing body of research has provided evidence that dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are involved in an organism's response to stress and that it may provide beneficial behavioral and neurotrophic effects. METHODS: This study investigated plasma DHEA and DHEAS, cortisol, psychological symptoms of dissociation, and military performance in 41 healthy active duty subjects enrolled in the military Combat Diver Qualification Course (CDQC). RESULTS: Baseline values of DHEA and DHEAS were significantly and positively predictive of superior performance in the underwater navigation exam; in addition, DHEA and DHEAS were significantly and negatively related to stress-induced symptoms of dissociation during performance of the task. Similarly, participants who reported fewer symptoms of dissociation exhibited superior military performance and increased levels of DHEA after the test. CONCLUSIONS: These data provide prospective, empiric evidence that DHEA and DHEAS are associated with superior stress tolerance, fewer symptoms of dissociation, and superior, objectively assessed, military performance.