Val/Val glutathione-S-transferase P1 polymorphism predicts nonresponders in psoriasis patients treated with fumaric acid esters

Abstract

Fumaric acid esters (FAE) are beneficial in the treatment of psoriasis. However, about a third of psoriasis patients do not respond to FAE. We aimed to determine whether glutathione-S-transferase (GST) M1 and GSTP1 polymorphisms are associated with treatment outcome in psoriasis patients treated with FAE. We studied 84 psoriasis patients who were treated with FAE for 3 months. FAE nonresponders were defined as having psoriasis area and severity improvement index less than 50% after 3-month therapy. GSTM1 genotyping for gene deletion and GSTP1 exon 5 105 Ile→Val polymorphisms were assessed using a high-resolution melting analysis. A dropout rate of 23.8% (20/84) was found; 25% (16/64) were FAE nonresponders. We observed 42 (84/50%) patients with G 9STM1*0 homozygous alleles and 42 (84/50%) patients with one or two active GSTM1 alleles. The Ile/Ile GSTP1 genotype was observed in 37 (84/44%), the Ile/Val GSTP1 genotype in 38 (84/45.2%) patients and the Val/Val GSTP1 genotype in nine (84/10.7%) patients. There was no significant (P>0.05) association between the GST genotypes assessed and the frequency FAE responder status, except for the Val/Val GSTP1 polymorphism, which was a significant (overall model fit; P=0.0012) predictor for nonresponders with an odds ratio of 43.4 (95% confidence interval: 4.2-511.1). The coefficient of regression was 3.9, with a SE of 1.2 as assessed by logistic regression analysis (P=0.0017). The Val/Val GSTP1 polymorphism predicts nonresponders in FAE treatment of psoriasis patients and may therefore serve as a biomarker that enables a laboratory-based pretreatment selection of patients.

Towards Personalized Medicine in Psoriasis: Current Progress

“…In detail, Gambichler et al investigated the role of glutathione-S-transferase (GST) M1 and GSTP1 polymorphisms in response to 3 month-treatment with DMF in 84 psoriasis patients. 40 They found out that the Val/Val GSTP1 polymorphism increased by 43 folds the risk of treatment failure (non-responders), while no association was reported for GSTM1. 40 Hence, the Val/Val GSTP1 polymorphism may be employed to screen for responders versus non-responders to DMT in the therapy decision process.…”

“… 39 At a molecular level, the immunomodulation derives from cellular glutathione depletion (and the induction of glutathione-S-transferase) and oxidative stress. 40 This drug showed a good efficacy and tolerable safety profile. 39 The most common AEs (flushing and gastrointestinal disorders) occurred mainly during the first few weeks of treatment and tended to improve or resolve over time.…”

Role of dimethyl fumarate in the treatment of glioblastoma multiforme: A review article

“… 16 DMF can easily enter cells as it is a highly lipophilic substance. 17 However, once DMF releases from its capsule (as a drug), it undergoes rapid pre-systemic hydrolysis with the help of ubiquitously-found esterases in GI tract, tissues, and blood. 18 , 19 The resulting active metabolite is monomethyl fumarate (MMF).…”

“…Glutathione S-transferases (GSTs) [GSTs are detoxification agents that are used as catalyzers to conjugate the reduced form of glutathione (GSH) to xenobiotic substrates] which are induced by DMF, were investigated in psoriasis and it has been observed that Val/Val GSTP1 polymorphism is associated with non-responsiveness to treatment with this FAEs. 17 This polymorphism has also been suggested as a potential biomarker predicting the status of responsiveness to DMF in other diseases. 17 There is no information about the impact of GBM heterogeneity on response to DMF therapy and comprehensive studies on this field are required.…”

“… 17 This polymorphism has also been suggested as a potential biomarker predicting the status of responsiveness to DMF in other diseases. 17 There is no information about the impact of GBM heterogeneity on response to DMF therapy and comprehensive studies on this field are required.…”