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

IF 3.7 4区医学 Q1 DERMATOLOGY Dermatologic Therapy Pub Date : 2024-11-17 DOI:10.1155/2024/5573157

Anfisa Lepekhova, Olga Olisova, Nikolay Shimanovsky, Natalia Teplyuk, Elizaveta Zhgelskaya, Ridhima Punj, Alina Mardanova, Alexander Dukhanin

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Abstract

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.

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糖皮质激素受体的 A3669G 多态性在丘疹性荨麻疹患者中比在健康对照组中更常见，并且有助于产生类固醇抗药性

糖皮质激素受体（GR）主要有两种异构体，即α异构体和β异构体。GRβ 异构体是 GRα 受体的主要抑制剂，在许多情况下对全身性糖皮质激素（GCs）反应不佳起着重要作用。人类 GR 非翻译区的 A3669G（rs6198）多态性（SNP）能稳定显性阴性 GRβ 异构体的 mRNA。然而，编码 GRβ 异构体的 mRNA 的生成机制尚不明确，尤其是在对 GCs 无反应的丘疹性荨麻疹患者中。我们的主要目的是研究寻常性天疱疮（PV）患者和健康对照者的 GR 基因 SNP。我们研究了人类 GRβ 基因的 A3669G SNP 是否是 PV 的易感等位基因，是否会导致 GC 抗药性的产生。我们通过高分辨率熔解分析确定了 A3669G SNP 的存在，然后通过直接测序进行了确认。与健康对照组（n = 92; 3.2%; p <0.001）相比，GR A3669G SNP（AG 基因型）更频繁地出现在 PV 患者中（n = 72; 25%）。等位基因 G 在帕金森病患者中的出现率明显更高（p <0.001）。在 48 名 A3669G SNP 基因型为 AA 的患者中，只有 6 人对 GC 产生耐药性，而在 18 名基因型为 AG 的患者中，有 11 人对 GC 产生耐药性（p < 0.0001）。与 AG 阴性组相比，AG 基因型患者对 GC 反应不佳的频率高出 4.89 倍（p < 0.0001）。我们的研究表明，A3669G SNP 更多出现在 PV 患者中。此外，AG 基因型患者的 GC 耐药性出现得更频繁（p < 0.0001）。由于那些以重症丘疹性荨麻疹为主的患者具有 GC 耐药性（p = 0.001），我们认为 A3669G SNP（AG 基因型）有助于丘疹性荨麻疹的发生。然而，还需要更多的研究来确定人类 GR 基因的 A3669G SNP 是否与这些患者的疾病严重程度和对 GCs 的不良反应有关。

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来源期刊

Dermatologic Therapy 医学-皮肤病学

CiteScore

7.00

自引率

8.30%

发文量

711

审稿时长

3 months

期刊介绍： Dermatologic Therapy has been created to fill an important void in the dermatologic literature: the lack of a readily available source of up-to-date information on the treatment of specific cutaneous diseases and the practical application of specific treatment modalities. Each issue of the journal consists of a series of scholarly review articles written by leaders in dermatology in which they describe, in very specific terms, how they treat particular cutaneous diseases and how they use specific therapeutic agents. The information contained in each issue is so practical and detailed that the reader should be able to directly apply various treatment approaches to daily clinical situations. Because of the specific and practical nature of this publication, Dermatologic Therapy not only serves as a readily available resource for the day-to-day treatment of patients, but also as an evolving therapeutic textbook for the treatment of dermatologic diseases.