Association between BclI polymorphism in the NR3C1 gene and in vitro individual variations in lymphocyte responses to methylprednisolone

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In vitro lymphocyte steroid sensitivity has been suggested as a useful tool to predict in vivo response to glucocorticoid treatment in different inflammatory chronic diseases. • A correlation between genetic polymorphisms and clinical response to glucocorticoids has been demonstrated in these patients. WHAT THIS STUDY ADDS • The BclI polymorphism in the glucocorticoid receptor (NR3C1) gene is associated with higher methylprednisolone potency in vitro. • The combined evaluation of the in vitro sensitivity to methylprednisolone and BclI polymorphism could represent an aid for physicians to adjust therapy a priori. AIM To evaluate the association between the in vitro sensitivity of peripheral blood mononuclear cells (PBMCs) to methylprednisolone (MP) and the presence of genetic polymorphisms involved in glucocorticoid (GC) response. METHODS In vitro MP inhibition of the proliferation of lymphocytes stimulated with concanavalin A was determined. Non linear regression of dose–response data was performed computing the MP concentration required to reduce proliferation to 50% (IC50). The maximum inhibition achievable at the highest MP concentration (Imax) was also calculated. Moreover, the Taqman technique was used to analyze the BclI polymorphism in the NR3C1 gene and the Leu155His polymorphism in the NALP1 gene. RESULTS A significant association between the BclI mutated genotype and an increased in vitro sensitivity to GCs was observed. CONCLUSIONS The a priori evaluation of the BclI polymorphism, associated with a lymphocyte proliferation assay, could represent a useful diagnostic tool for the optimization of steroid treatment.

Genetic associations of the response to inhaled corticosteroids in children during an asthma exacerbation

“…In a small study, the frequency of the G allele was found to be significantly higher in the asthmatic population compared to controls (25). Even more relevant to our results is the observation that G allele was associated with hypersensitivity to glucocorticoids (26)(27)(28). Hence, it can be speculated that the increased sensitivity associated with the G allele of the rs41423247 may account for the better response of the asthmatic children carrying this allele.…”

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

“…In a large group of Dutch elderly individuals, subjects with the G allele had lower cortisol levels after dexamethasone suppression test as well as a tendency towards a decreased lean body mass and abdominal fat distribution, high blood pressure, altered insulin sensitivity, and cardiovascular risk factors, suggesting hypersensitivity to GC (38). In 42 blood donors, association between the BclI variant genotype and an increased in vitro sensitivity to GCs was observed by DEX-mediated inhibition of concanavalin-A-stimulated PMBC (40). On the contrary, our data show no differences in BMI, Kd, IC 50 , and early morning serum or salivary cortisol concentrations at baseline and after dexamethasone suppression tests among BclI genotype groups.…”

Personalized Therapies in Pediatric Inflammatory and Autoimmune Diseases

“…Furthermore, within-individual variation in lymphocyte sensitivity, expressed as maximum inhibition achieved (Imax), is low, and the degree of resistance in a given individual remains relatively constant over time, at least for healthy subjects [25]. In addition, a recent study [13] has shown an association between the BclI mutated genotype, in the GR gene, previously associated with a better response to glucocorticoids in pediatric patients with inflammatory bowel disease [17,26], and an increased in vitro sensitivity to glucocorticoids in healthy subjects. Of particular interest are the observations that the results of this pharmacodynamic in vitro test can be correlated with the clinical response to glucocorticoids in different diseases such as rheumatoid arthritis [27,28], systemic lupus erythematosus [29], bronchial asthma [30][31][32][33], renal transplant rejection [34] and ulcerative colitis [12,35].…”

“…For pediatric inflammatory and autoimmune disease, the issue may be the collection of a tissue representative of the disease condition and suitable for a pharmacodynamic assessment. However, there are reports that primary cultures of peripheral leukocytes may be suitable for these assays, even in pediatric inflammatory diseases [12,13].…”