There is strong evidence linking psychological stress, HPA-axis activity, and the immune system dysregulation with negative health outcomes. For example, chronic stress, HPA-axis and immune system dysfunction are all associated with greater risk of infection and diagnosis of chronic inflammatory disease, autoimmune disease, depression, and anxiety. Yet, some individuals do not develop significant health issues and instead demonstrate great resilience under these same stressful environments. The factors or mechanisms that contribute to this variability remain to be determined. Understanding these influences and how they relate to both psychological and physiological changes are especially important for current and forthcoming research on intervention, prevention and clinical application. The following dissertation contains two related studies that together are guided by a gene x environment interaction approach aimed at understanding important unanswered questions regarding the relative and collective contributions of fragile X mental retardation 1 (FMR1) genotype and psychological stress on two important physiological systems, the HPA-axis and immune system. In the first study (Chapter 2), we examined how the relationship between FMR1 genotype and immunological functioning is moderated by self-reported psychological stress. Much of the research and theory thus far has focused on FMR1 gene expression-related pathogenic mechanism (i.e. mRNA toxicity) as the cause of various negative health outcomes associated with FMR1 alleles in the premutation range. Moreover, previous work has disproportionately focused on mothers caring for a son/daughter with FXS who are known to be greatly affected by caregiving-associated chronic stress. Therefore, an important goal of this first study was to determine the extent to which the effect of self-reported stress differentially affects the association between FMR1 genotype and immune functioning by oversampling women with the premutation who are not caregivers of affected children. Another important feature of the first study was the focus on underlying biologically-based endophenotypes instead of diagnostic categories. Women with activation ratio-corrected CGG (AR-CGG) repeat lengths in the mid-premutation range (around 60-80 AR-CGG repeats) were more sensitive to the effects of psychological stress, such that women in this range with higher levels of stress display higher levels of IL-10 and lower levels of Th1-associated cytokines. In part, these findings differ from previous research demonstrating more broad suppression of cytokine production among women with FMR1 alleles in the premutation range. However, our results are consistent with previous findings of a Th1/Th2 shift in the immune system reported to be associated with stress. Specifically, higher levels of cortisol are thought to shift the balance toward more Th2-associated cytokines. This type of immunological imbalance is observed in fibromyalgia, atopic dermatitis, asthma, anxiety and depression. This may in part explain why women with the premutation are also more likely to experience some of these health issues. Our second study (Chapter 3) focuses on how psychological stress and FMR1 genotype interact and affect HPA-axis activity. This study was a natural extension of the first, namely by determining whether HPA-axis activity, which has been shown to be dysregulated in women with certain FMR1 alleles, mediates the association between FMR1 genotype and immune system dysregulation. We found that among women with AR-CGG lengths greater than 80 repeats, higher levels of self-reported stress were associated with elevated waking cortisol levels and flatter diurnal slopes. Additionally, we observed a curvilinear association between AR-CGG repeat size and waking cortisol which was moderated by stress. Women with FMR1 alleles in the 60-80 AR-CGG repeat range were more sensitive to the effect of negative life events displaying elevated waking cortisol. Our moderated-mediation analysis found no mediating effect of HPA-axis activity between stress and FMR1 genotype with immune system functioning. In sum, women with FMR1 alleles in the mid-premutation range were found to be more sensitive to the effects of stress on diurnal cortisol. These findings have implications for understanding the association between the FMR1 gene and the increased risk of developing depression, anxiety, and various inflammatory/autoimmune disorders among women with the premutation. In total, the goal of these two studies was to implement a gene-environment interaction approach in order to; (a) determine the extent to which the susceptibility of developing immune system dysregulation among certain FMR1 alleles is regulated at least in part by psychological stress and (b) determine whether diurnal HPA-axis dysregulation is a possible biological mechanism underlying this relationship. The results of these studies have the potential to impact society in a variety of ways. First, the findings from these two studies can advance our general understanding of basic biological processes underlying why and how the environment in which we live and develop gets “under the skin” affecting two important physiological systems and overall health. Second, these findings have the capacity to inform a substantial portion of the population (1 in 113-152 women are FMR1 premutation carriers), indicating that the FMR1 gene may be an important contributor to immune dysregulation in the general population. Finally, counseling and preventative research will benefit from a better understanding of when and how stress can affect individuals who might be more genetically vulnerable.
|Commitee:||Ashwood, Paul, Hibel, Leah, Liu, Siwei, Tassone, Flora|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 77/04(E), Dissertation Abstracts International|
|Keywords:||Dysfunction, Fmr1, Gene-environment, Hpa-axis, Immune, Stress, Susceptibility|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be