A3669G Polymorphism of Glucocorticoid Receptor Is More Present in Patients With Pemphigus Vulgaris Than in Healthy Controls and Contributes to Steroid-Resistance

There are two main isoforms of glucocorticoid receptor (GR) α- and β-isoforms. GRβ isoform is the dominant inhibitor of the GRα receptor and plays a significant role in a poor response to systemic glucocorticoids (GCs) under numerous conditions. The A3669G (rs6198) polymorphism (SNP) in the untranslated region of human GR stabilizes the mRNA of the dominant-negative GRβ isoform. However, the mechanisms which generate mRNA encoding the GRβ isoform have been poorly defined, especially in pemphigus patients who do not respond to GCs. The main aim was to study gene SNP of GR in patients with pemphigus vulgaris (PV) and healthy controls. We investigated whether the A3669G SNP of the human GRβ gene is a susceptibility allele for PV and contributes to GC resistance development. The presence of the A3669G SNP was determined by high-resolution melting analysis and then confirmed by direct sequencing. GR A3669G SNP (AG genotype) occurred more frequently in PV patients (n = 72; 25%) compared with healthy controls (n = 92; 3.2%; p < 0.001). Allele G was significantly more presented in PV patients (p < 0.001). Out of 48 patients with AA genotype of A3669G SNP, only 6 had GC resistance, whereas 11 out of 18 with AG genotype developed GC resistance (p < 0.0001). The frequency of a poor response to GC in the group of patients with AG genotype was 4.89 times higher compared to AG negative one (p < 0.0001).

Our study showed that the A3669G SNP was more present in PV patients. Moreover, GC resistance appeared more frequently in patients with the AG genotype (p < 0.0001). Since those patients predominantly with severe pemphigus had GC resistance (p = 0.001), we feel that A3669G SNP (AG genotype) contributes to its development. However, more studies are needed to determine whether A3669G SNP of the human GR gene associated with the disease severity and poor response to GCs in these patients.