Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes

Abstract

The clinical presentation of asthma results from complex gene-gene and gene-environment interactions. The natural variability of the DNA sequence within the NR3C1 gene affects the activity of glucocorticoid receptors (GCRs). The NR3C1 gene is localized on chromosome 5q31–q32. The gene coding for the GCR comprises nine exons. The structural domains of the GCR determine the biological functions of the functional domains. The observed resistance to glucocorticosteroids and the normal metabolic profile of Tth111I single nucleotide polymorphism (SNP) carriers is due to the ER22/23EK polymorphism that is present in them. BclI polymorphism significantly affects the process of alternative NR3C1 gene splicing and within that mechanism increases the sensitivity to glucocorticoids (GCs). A total of 451 subjects were enrolled in the present study, including 235 qualified to the group of bronchial asthma patients. A group of 216 healthy participants with no history of asthma or atopic conditions was qualified for the study. Genotyping was accomplished using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR-high resolution melting (HRM) methods. No statistically significant differences were observed in the frequency of Tth111I, BclI and ER22/23EK polymorphisms of the NR3C1 gene when comparing mild, moderate and severe asthma vs. the control group. Investigative analyses demonstrated statistically significant correlations for alleles and genotypes of Tth111I polymorphism of the NR3C1 gene between healthy subjects and patients with severe asthma characterized by a control profile corresponding to an Asthma Control Test (ACT)™ score ≥20. It was established that only the Tth111I polymorphism of the NR3C1 gene plays an important role in the pathogenesis of chronic bronchitis leading to the development of asthma with both allergic and non-allergic etiology.

Identification and association of relationships between selected personal and environmental factors and formal components of temperament and strategies of coping with stress in asthmatic patients

“…Asthmatic [9,10,11,19,20,21,22,40]. The patients who had been diagnosed with chronic obstructive pulmonary disease, cardiac failure of III and IV class according to the NYHA Functional Classification, renal failure, liver insufficiency, thyroid diseases, diabetes, autoimmune diseases, neoplastic diseases, unstable angina pectoris and other severe systemic diseases, were excluded from the study.…”

“…The control group consisted only of healthy subjects who met all the required criteria: negative results of skin prick tests for common allergens, lack of first degree relatives with asthma, allergy or atopy, lack of therapy with rifampicin, phenobarbital, phenytoin or ephedrine, lack of a physical examination and anamnesis confirming the occurrence of asthma, other pulmonary diseases, allergy, atopy and hypersensitivity to non-steroidal anti-inflammatory drugs and lack of a spirometric test confirming obturation [9,10,11,19,20,21,22,40].…”

“…Researchers discovered that a number of glucocorticoid receptors (GR) in cells as well as their function is reduced in patients with mood disorders [18]. Expression of GR is determined and regulated by glucocorticoid receptor gene NR3C1 (nuclear receptor subfamily 3, group C, member 1 gene) [19,20,21]. They also observed that there is a relationship between haplotypes of NR3C1 gene and depression and anxiety [22].…”

Correlation between polymorphisms in the glucocorticoid receptor gene NR3C1 and susceptibility to asthma in a Chinese population from the Henan Province

“…Previous studies (van Rossum and Lamberts, 2004;De Iudicibus et al, 2011;Panek et al, 2013a) reported an association between the Tth111I SNP and increased cortisol level in the blood; additionally, these studies reported a decrease in the cortisol secretion following the administration of 1 mg dexamethasone (DEX). Additionally, carriers of the Tth111I SNP who also express the ER22/23EK SNP have been shown to induce resistance to GCs and show a normal metabolic profile Nicolaides et al, 2010;Panek et al, 2012a).…”

“…Tth111I is a restriction fragment length polymorphism (RFLP) that is coupled with the ER22/23EK SNP (rs6189 and rs6190) (Detera-Wadleigh et al, 1991;Rosmond et al, 2000;DeRijk and de Kloet, 2008;Nicolaides et al, 2010;Panek et al, 2013a). The C/G SNP in BclI (rs41423247) is associated with increased cortisol suppression (van Rossum et al, 2003;Stevens et al, 2004), while ER22/23EK (rs6189 and rs6190) (Koper et al, 1997) is believed to be associated with decreased GR sensitivity (van Rossum et al, 2002.…”