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    • The ER EK polymorphism is located in the transactivation dom

    2021-11-22

    The ER22/23EK polymorphism is located in the transactivation domain of the GR gene. A single nucleotide polymorphisms (SNPs) has been identified in both of the two adjacent codons (22 and 23). These SNPs are fully linked and are associated with relative GC resistance[32], [44]. Although no associations with body mass index or fat mass has been found, the lean body mass was significantly higher in male carriers of the ER22/23EK polymorphism [45]. Increased muscle strength was also found in those men. In women, no statistically significant differences in BMI were found but a smaller waist circumference was observed in ER22/23EK carriers. Another striking anthropometric difference that has been observed in several studies between carriers and non-carriers of the ER22/23EK polymorphism is that male ER233/23EK carriers were found to be taller than non-carriers. Male ER22/23EK carriers were also found to have increased insulin sensitivity, lower fasting insulin levels, lower C-reactive protein and lower total and LDL cholesterol levels [46]. Finally, the 9β polymorphism of the GR Gene has not been linked with BMI, adipose mass changes, waist to hip ratio, insulin sensitivity, LDL and HDL cholesterol levels. Although no significant differences were observed in anthropometric characteristics, subjects homozygous for the 9β variant had increased intima media thickness and an almost three fold increased risk for cardiovascular disease, most likely due to a subtle but chronic pro-inflammatory state [47]. This 9β polymorphism results in an increased expression and stabilization of GRβ which functions as an active inhibitor of the active form, GRα [48]. Although the transactivation of the GR is not affected by the 9β polymorphism, transrepression is significantly reduced, and a pro-inflammatory state is expected-due to a more active immune system- in the 9β carriers [49].
    The role of glucocorticoid receptor in psychiatric illness It has long been hypothesized that the development of psychotic symptoms in Psychotic Depression (PD) is related to increased or dysregulated systemic entacapone levels, leading to increased dopamine levels and changes to dopamine metabolism, which potentially induce psychotic symptoms in susceptible individuals [50]. Biologic findings in patients with PD related to elevated and dysregulated cortisol levels include high rates of non-suppression on the DST [51], reduced diurnal fluctuation of cortisol, high plasma cortisol and ACTH levels, and increased excretion of 24h urinary free cortisol [52], [53]. The mRNA expression of the GRα is reduced in lymphocytes of patients with major depressive disorder, both while they are depressed and when their depression is in remission. The same pattern of reduced GRα mRNA is found in first-degree relatives of patients with bipolar disorder. Those HPA axis abnormalities, at least at the GR level, could represent a trait marker for mood disorders [54]. Patients with depression and history of childhood abuse have enhanced HPA axis responses to psychosocial stress [55] and blunted adrenocorticotropin and cortisol response to low-dose dexamethasone. Those findings were not present in the non-depressed patients with a history of childhood abuse [56]. Cortisol responses to dexamethasone/CRH challenge in healthy subjects with high genetic load for affective disorders lies between the responses of healthy subjects without a family history of depression and those of depressed patients suggesting that genetic vulnerability may be intertwined with early life experience to produce to the final expression of the disease [57], [58]. All carriers of the ER22/23EK polymorphism carry the TthIIII minor allele and demonstrate reduced GC sensitivity. An increased risk of developing depression has been reported in subjects with smaller hippocampal size which is more prevalent in homozygous carriers of the TthIIII polymorphism [59], [60]. The observation of smaller hippocampal volumes in TthIIII polymorphism carriers suggests a link between the TthIII I polymorphism and unipolar depression. Conversely, a lower prevalence of heterozygous TthIII I polymorphism carriers was found in bipolar disorder patients [61]. This may suggest a trend towards a protective effect on the clinical manifestations and course of bipolar disorder in TthIIII polymorphism carriers [55].