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• W2296937301 abstract "Oxidative stress is considered to be the initial pathogenic event in melanocyte destruction in vitiligo 1. Previous studies have demonstrated decreased GPX activity in epidermis 2, PBMCs 3, whole blood 4 and erythrocytes 5 and increased erythrocyte LPO levels in patients with vitiligo 5-7. GPX1 is a major intracellular antioxidant enzyme, and its Leu200Pro (rs1050450) polymorphism has been widely reported to be associated with decreased activity in different diseases 8, 9. However, in our previous study this SNP was found to be uninformative in vitiligo 7. Therefore, we hypothesized that other polymorphism(s) might be responsible for the decreased GPX1 activity in patients with vitiligo. In the present study, SNPs were selected based on in silico analysis. We performed sequence-based analysis to predict the impact of GPX1 exon1 G/C (rs8179169; Arg5Pro) and T/C (rs4991448; Leu6Pro) and exon2 C/T (rs6446261; Ala194Thr) polymorphisms on GPX1 protein using bioinformatics tools, which revealed decreased stability of Leu6Pro and Ala194Thr variants consecutively influencing GPX1 function, whereas Arg5Pro and Leu6Pro variants were found to be disease-related (Table S1). The present study aimed (i) to investigate GPX1 Arg5Pro, Leu6Pro and Ala194Thr polymorphisms; (ii) to estimate erythrocyte GPX1 activity and LPO levels; (iii) to estimate GPX1 transcript levels in PBMCs from patients with vitiligo and controls from Gujarat population; and (iv) to analyse the structural and functional impacts of these variations on GPX1 protein using in silico tools. Described in ‘Data S1’. GC (Arg/Pro) and TC (Leu/Pro) genotypes of Arg5Pro and Leu6Pro polymorphisms respectively were found to be significantly associated with vitiligo (P < 0.0001, P < 0.0001; Table 1). In particular, minor allele ‘Pro’ for both the SNPs was prevalent in patients compared to controls (P = 0.0002, P < 0.0001), specifically in patients with active vitiligo (AV) compared to controls (P < 0.0001, P < 0.0001) and in patients with AV compared to patients with stable vitiligo (SV) (P = 0.013, P = 0.007), suggesting the importance of ‘Pro’ allele in disease progression. Further analysis based on the type of vitiligo revealed that the increased frequency of the minor allele ‘Pro’ for both the SNPs occurred predominantly in patients with GV (P < 0.0001, P = 0.001) compared to controls. Interestingly, the ‘GC’ genotype of Arg5Pro polymorphism was predominant in patients with GV compared to patients with LV (P = 0.015), suggesting its importance in GV. On the other hand, the ‘Pro’ allele of Leu6Pro polymorphism was predominant in patients with LV compared to controls (P < 0.0001), suggesting its importance in LV. Moreover, analysis based on gender revealed an increased frequency of the ‘GC’ genotype in male patients (P = 0.014) compared to female patients. However, for Ala194Thr (C/T) polymorphism only C (Ala) allele was found to be present in patient and control groups (Fig. S1). 0.013b <0.0001c 0.516d 0.015e <0.0001f 0.551g 0.027b <0.0001c 0.546d 0.0296e <0.0001f 0.578g 0.011b <0.0001c 0.444d 0.321e 0.0003f 0.0003g 0.139b 0.044c 0.7133 0.155e 0.456f 0.027g 0.007b <0.0001c 0.641d 0.153e 0.001f <0.0001g Arg5Pro and Leu6Pro polymorphisms investigated in the GPX1 were in moderate LD (D'=0.675, r2=0.352). Haplotype frequencies differed significantly between patients and controls (global P value = 3.53e−009; Table S5). Interestingly, the frequency of susceptible haplotype ‘Pro+Pro’ containing the minor alleles of both polymorphisms was significantly higher in patients compared to controls (P = 0.006) and showed a 1.5-fold increased risk of vitiligo. Also, ‘Pro+Leu’ and ‘Arg+Pro’ haplotypes were significantly higher in patients with vitiligo compared to controls (P = 0.0004, P = 5.09e−005). PANTHER tool showed that Arg5Pro, Leu6Pro and Ala194Thr variations might be deleterious to GPX1 function, with highest score of -4.78994 and probability of ~86% for Leu6Pro variation (Table S1). I-MUTANT and MUPRO predictions revealed decreased stability of Leu6Pro and Ala194Thr variants compared to native, which might in turn affect GPX1 activity. SNP AND GO tool, which predicts whether a mutation at the protein level is or is not disease-related, revealed that Arg5Pro and Leu6Pro variants are disease-related. Molecular dynamics simulation was performed to investigate the structural differences as well as stability of GPX1 wild, Arg5Pro and Leu6Pro variants, which revealed altered backbone stability of GPX1 with Arg5Pro and Leu6Pro variants compared to wild type (Figs S3, S4 and S5). Detailed results are described in ‘Data S1’. Patients showed a 1.93-fold decreased GPX1 activity compared to controls (P < 0.0001; Fig. 1a). Interestingly, patients with AV showed a significant decrease in GPX1 activity compared to patients with SV (P = 0.007), suggesting the involvement of GPX1 in disease progression. Moreover, GPX1 activity was significantly decreased in patients with GV compared to patients with LV (P < 0.0001) and in male patients compared to female patients (P = 0.0358). However, GPX1 transcript levels did not differ significantly between patients and controls (0.768-fold change; P = 0.378), suggesting the functional alteration of the GPX1 (Fig. S2). Patients showed ~1.54-fold increased LPO levels compared to controls (P < 0.0001; Fig. 1b), suggesting increased oxidative stress in vitiligo. LPO levels were also increased significantly in patients with GV compared to patients with LV (P = 0.001) and in patients with AV compared to patients with SV (P < 0.0001), suggesting the involvement of oxidative stress in disease progression. Individuals with Arg/Pro genotype for Arg5Pro polymorphism showed significantly decreased GPX1 activity (P < 0.0001) compared to individuals with Arg/Arg genotype (Fig. 1c). In case of Leu6Pro SNP, Pro/Pro and Leu/Pro genotypes showed significantly decreased GPX1 activity (P = 0.0004; P < 0.0001) compared to Leu/Leu genotype. Further, Pro/Pro genotype showed significantly decreased GPX1 activity (P = 0.0449) compared to Leu/Pro genotype. Interestingly, individuals with Arg/Pro genotype showed significantly increased LPO levels (P = 0.006; Fig. 1d) compared to individuals with Arg/Arg genotype. In case of Leu6Pro SNP, Pro/Pro and Leu/Pro genotypes showed significantly increased LPO levels (P = 0.023; P = 0.026) compared to individuals with Leu/Leu genotype. However, Pro/Pro genotype did not show any significant difference in LPO levels (P = 0.328) compared to Leu/Pro genotype. Our results are in agreement with previously reported altered systemic antioxidant pattern in vitiligo patients with reduced GPX, catalase and G6PD activities along with decreased GSH levels and increased SOD activity, which were correlated with higher LPO levels 4, 6, 7. Overall, the present study for the first time confirms the genetic association of vitiligo with variations in GPX1, which contains at least two independent risk signals, one tagged by Arg5Pro SNP and another tagged by Leu6Pro. The study also emphasizes the influence of these SNPs on decreased GPX1 activity in patients, which was further supported by simulation studies, suggesting the crucial role of genetic factors and oxidative stress in vitiligo pathogenesis. This work was supported by grants to RB (“BT/PR9024/MED/12/332/2007”) from DBT, New Delhi, India. We sincerely thank all patients with vitiligo and control subjects for their participation in this study. MSM thanks UGC, New Delhi, for awarding JRF. MSM and DP performed the research; RB, MSM, NCL, MD and DDS designed the research study; RB and DDS contributed essential reagents or tools; MSM, MD, TA and MS analysed the data; and MSM, MD and RB wrote the manuscript. All authors declare no conflict of interest. Table S1.In silico prediction analysis for GPX1 polymorphisms. Table S2. Demographic characteristics of patients with vitiligo and unaffected controls. Table S3. Primers and restriction enzymes used for GPX1 expression and SNP genotyping. Table S4. Distribution of genotype and allele frequencies for GPX1 polymorphisms in male and female patients with vitiligo. Table S5. Distribution of haplotype frequencies for GPX1 polymorphisms in patients with vitiligo and controls. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2296937301 date "2016-05-19" @default.
• W2296937301 modified "2023-09-27" @default.
• W2296937301 title "Genetic variations (Arg5Pro and Leu6Pro) modulate the structure and activity of GPX1 and genetic risk for vitiligo" @default.
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