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These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.
Based on the compelling body of preclinical work, the two previous studies in humans, and our prior findings of enduring neuroendocrine alterations in adults with a history of childhood adversity, we conducted the present study to test the hypothesis that increased leukocyte NR3C1 promoter methylation is associated with adverse childhood experiences and with attenuated cortisol responses to a standardized neuroendocrine challenge test. We report here that childhood adversity is associated with greater NR3C1 methylation, and that individuals with greater levels of NR3C1 methylation have attenuated cortisol responses to the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test.
We found that healthy adults reporting a history of childhood adversity (loss of a parent, maltreatment, poor quality parenting) had increased cytosine methylation of the promoter region of the GR gene NR3C1. In addition, methylation of this region was associated with attenuated cortisol responses to the Dex/CRH test in adulthood. This is the first study to demonstrate that variation in human parenting experiences is linked to epigenetic modulation of the leukocyte GR gene. Our results are consistent with findings of the two prior human studies (using hippocampal tissue and infant cord blood, respectively) of epigenetic modulation of this gene in association with childhood maltreatment  and prenatal exposure to maternal depressed mood . In rodents, low levels of maternal care during early postnatal life are associated with increased cytosine methylation and decreased expression of the hippocampal GR (NR3C1) promoter . Given previous findings on childhood maltreatment and loss on risk for psychopathology, the effect of promoter methylation on GR expression and glucocorticoid responses, and the role of HPA axis dysfunction in depressive and anxiety disorders, the present findings suggest that epigenetic changes to this gene could be a key mechanism for effects of childhood adversity on risk for these disorders.
Our findings of greater methylation at CpG 1 in association with low Parental Care and with loss of a parent in childhood also extend the findings of Oberlander and colleagues  of increased infant methylation of CpG 1 in association with maternal depressed mood in the third trimester. The additive Adversity Index was also positively correlated with both CpG 1 and 3, indicating that a greater number of different adverse childhood experiences is associated with more methylation at NR3C1. Our findings appear to be specific to early environment stress and are not accounted for by current psychopathology or subsyndromal symptoms.
In this study we examined the leukocyte GR gene, whereas the previous human investigations of the effect of exposures examined cord blood or hippocampal tissue. The similarity of our findings to those of the prior human studies, as well as animal work on the hippocampal GR in relation to variation in maternal care, is encouraging, but data regarding the differential control of expression of the GR in various tissues are very limited. Some evidence indicates similarities in the regulation of this gene in brain and peripheral tissues. Lee and colleagues  found that chronic oral corticosterone administration caused anxiety-like behavior and a decrease in hippocampal and blood mRNA levels of NR3C1. Moreover, the relevance of regulation of leukocyte glucocorticoid receptor expression for stress-related disorders is supported by evidence of abnormal sensitivity and expression of this receptor in leukocytes of patients with major depression and post-traumatic stress disorder , .
Our findings of age-related alterations to the extent of methylation are consistent with other reports that identify gene-specific associations between methylation and aging , . In addition, in this sample, older subjects reported higher levels of Maltreatment and lower Parental Care than younger participants (and age was controlled in the analyses). This may be a cohort effect, but it is possible that it is due to an age-related reporting or memory bias. We studied several related childhood experiences that commonly co-occur and may have similar or redundant epigenetic effects. It is notable that the Adversity Index, the sum of the various childhood adversities, was positively associated with the degree of NR3C1 methylation. Childhood parental loss, which represents a more objective event than some other types of experiences and is less likely to co-occur with maltreatment than other forms of adversity, was the strongest predictor of CpG methylation (and was not associated with age). It should be noted that the effects of childhood parental loss may be mitigated by personal and familial characteristics that influence adaptation to loss (e.g., , ).
Because we studied a mixed population of leukocytes, our findings could be influenced by the relative composition of these cells, which can be altered during infection and other conditions. Glucocorticoids have strong anti-inflammatory effects, and glucocorticoid receptors are present in several leukocyte cell types, including lymphocytes, neutrophils, eosinophils, and macrophages . However, it is unlikely that inflammatory conditions explain our findings because 1) we excluded subjects with acute or chronic illness, allergy symptoms, abnormal blood counts, or the use of antibiotics, antihistamines, or corticosteroids, and 2) any such confounding effect would have to occur differentially in those with adversity.
In summary, we found that early-life stress, in the form of loss of a parent during childhood, maltreatment, and low parental care, was associated with epigenetic changes to the promoter region of the glucocorticoid receptor gene. In addition, methylation of the promoter region of this gene was linked to alterations in HPA axis function. These findings, together with previous research in rodents and two prior studies in humans, provide preliminary support for the hypothesis that altered expression of the glucocorticoid receptor due to cytosine methylation of the gene promoter could be a mechanism of the neuroendocrine effects of early-life stress, and could predispose to the development of major depression and post-traumatic stress disorder. However, our effect sizes tended to be modest in magnitude, different CpG sites were associated with the associations of childhood adversity measures and the cortisol response to the Dex/CRH test, and we did not have gene expression data available. This study will need to be replicated in order to draw firm conclusions about the findings. Further work is also needed to determine whether these findings are specific to lymphocytes and whether this reflects changes in central regulation of the glucocorticoid receptor in brain regions involved in stress responses and mood and anxiety disorders.
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Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.
In total, 88 different rare manifestations were recorded in 17.3% of patients in this study. This shows the complexity of the disease and highlights the limitations of systematic evaluation and treatment of rare manifestations. Most rare manifestations were more common in female patients and those with TSC2 mutations, which is in line with findings from previous literature on rare manifestations such as lymphedema and angiomyolipoma [10, 18]. Tumors and cystic lesions in a broad variety of organs seem to occur (or at least are detected) at higher ages. However, clinical significance seems limited in most cases, as treatment was reported for only 16% of tumors and 5% of cysts. It is worth noting that treatment rates differed markedly depending on organ system. Details are given in Additional File 1: Table S1. 2b1af7f3a8