title: The N363S and I559N single nucleotide polymorphisms of the h-GR/NR3C1             gene in patients with bronchial asthma.
abstract: Bronchial asthma is a disease of multifactorial etiology. The natural variability of the DNA sequence within the h-GR/NR3C1 gene affects both the conformation and the activity of glucocorticoid receptors. There are 2 major types of resistance to glucocorticoids (GCS)-resistant asthma failing to respond to treatment with high doses of inhaled and oral glucocorticoids. Type I GCS-resistant asthma is cytokine-induced or acquired. Type II GCS resistance involves generalized primary cortisol resistance, which affects all tissues and is likely to be associated with a mutation in the glucocorticoid receptor (GCR) gene or in genes that modulate GCR function. There are clear examples of glucocorticoid gene h-GR/NR3C1 polymorphisms that can influence responses and sensitivity to glucocorticosteroids. Among the numerous polymorphisms observed within this gene, N363S and I559N single nucleotide polymorphisms (SNPs) may play an important role in the development of bronchial asthma and in the alteration of sensitivity to GCS in severe bronchial asthma. The aim of this research project was to study the correlation between the N363S and I559N polymorphisms of the h-GR/NR3C1 gene and the occurrence of asthma in a population of Polish asthmatics. Peripheral blood was obtained from 210 healthy volunteers and 234 asthma patients. Structuralized anamnesis, spirometry and allergy skin prick tests were performed in all participants. Genotyping was carried out using the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR-HRM methods. In the healthy, non-atopic population, the GG variant of the N363S polymorphism was found with a 5.7% frequency. In asthma patients, GG SNP of N363S occurred with the frequency of 6.4%. In the groups of patients with uncontrolled moderate asthma and uncontrolled severe disease, the genotype distribution for the investigated polymorphisms were as follows: N363S, AA, AG, GG occurring with 0.8750/0.0834/0.0416 frequency and I559N, TT, TA, AA occurring with 1.000/0.000/0.000 frequency. The analysis demonstrated a significantly higher frequency of the A and G variants of the N363S polymorphisms in uncontrolled moderate asthma and uncontrolled severe disease than in the healthy population. No variant-related differences in the frequency of the studied I559N polymorphism were demonstrated in healthy controls and asthma patients. In conclusion, the N363S polymorphism of the h-GR/NR3C1 gene is significantly associated with an increased sensitivity to glucococorticoids in vivo and susceptibility to the development of a moderate to severe form of uncontrolled bronchial asthma in the Polish population. This observation needs to be confirmed in a larger group of subjects.
authors.affiliation: Department of Internal Medicine, Asthma and Allergy, Medical                     University of Lodz, Lodz, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Panek
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pietras
authors.forename: Adam
authors.initials: A
authors.lastname: Antczak
authors.forename: Artur
authors.initials: A
authors.lastname: Fabijan
authors.forename: Marcelina
authors.initials: M
authors.lastname: Przemęcka
authors.forename: Paweł
authors.initials: P
authors.lastname: Górski
authors.forename: Piotr
authors.initials: P
authors.lastname: Kuna
authors.forename: Janusz
authors.initials: J
authors.lastname: Szemraj
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D018927:Anti-Asthmatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D018808:Transcription Factor AP-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D016328:NF-kappa B; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1