POLYMORPHISMS OF GLUTATHIONE S-TRANSFERASE M1 AND T1: GENETIC RISK FACTOR FOR VITILIGO

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Introduction: vitiligo is the result of the interaction of genetic, biochemical, environmental and immunological factors. Oxidative stress has a significant pathogenic role in vitiligo, and is …

Introduction: vitiligo is the result of the interaction of genetic, biochemical, environmental and immunological factors. Oxidative stress has a significant pathogenic role in vitiligo, and is normally contrasted by various non-enzymatic and enzymatic antioxidant systems, including glutathione S-transferases (GSTs). The “null” allele (which causes the lack of production of the corresponding protein) of GST isoforms M1 and T1 may be found, with inter-ethnically variable frequency, in a relevant part of the general population, and is associated to various oxidative-stress related diseases.
Aims & Scope: to define the prevalence of GSTM1 and GSTT1 null polymorphisms in vitiligo patients and healthy controls from Sicily and Calabria, and the correlation of such genotypes with the disease.
Material and Methods: polymerase chain reaction was performed on buccal swabs of 58 non-segmental vitiligo patients (28 males, 30 females) and 150 healthy controls (71 males, 79 females) to define their GSTM1 and GSTT1 genotype (null/active).
Results: the GSTM1/GSTT1 double-null genotype is significantly more frequent in vitiligo patients than in controls (p=0.041), while this is not true for either single-null genotype. Neither the GSTM1 genotype nor the GSTT1 genotype are correlated to the disease.
Comments: the two other papers on GSTM1/GSTT1 genotype and vitiligo agree with our data for which concerns the association of the double-null genotype with a significantly increased risk for the disease, while they differ about disease correlation with either GST null genotype (GSTM1 in one paper, GSTT1 in another, none of the above in our casuistic). Discrepancies are probably due to a different “genetic setup” of the populations studied, which determines a different relative importance of GSTM1 and GSTT1 in the global balance of the antioxidant system. Thus, possession of the null allele for one GST isoform can variably increase the risk for vitiligo, depending on the relative importance of that isoform, while the reduction of the antioxidant potential due to the simultaneous lack of both GST isoforms (double null genotype) is significant in any configuration of the antioxidant system and always constitutes a risk factor for the disease.
Oxidative stress and antioxidant response could be linked to the dysregulated response observed in vitiligo. As suggested in a recent paper, cultured keratinocytes derived from vitiligo patients have higher levels of reactive oxygen species (ROS) and a characteristic dysregulation of the cytokine, chemokine and growth factor pattern.
Future perspectives include :
- GST genotyping of other populations, ethnically different from those currently described in literature, because of the high variability of the frequency of GST - Disclaimer-

This PPT is loaded as student material "as is", from the VRF Vitiligo Master Class Barcelona November 2011; VRF does not endorse or otherwise approve it.

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  • 1. POLYMORPHISMS OF GLUTATHIONE S-TRANSFERASE M1 AND T1: GENETIC RISK FACTOR FOR VITILIGO Fabrizio Guarneri 1 , Alessio Asmundo 2 , Daniela Sapienza 2 , Serafinella Patrizia Cannavò 1 1 Section of Dermatology and 2 Section of Legal Medicine, Department of Territorial Social Medicine, University of Messina, AOU “G. Martino”, Messina, Italy The International School of Vitiligo and Pigmentary Disorders Barcelona, 2-5 November 2011
  • 2. GLUTATHIONE S-TRANSFERASE
  • 3.
    • Enzymes for detoxification of electrophyle compounds by conjugation with glucuronates
    • Frequent genetic polymorphism
    • Main groups of polymorphisms: GSTA, GSTM, GSTP, GSTT
    • The “null” genotype of GSTM1 and GSTT1 can be found in a significant part of the general population
    GLUTATHIONE S-TRANSFERASE
  • 4. NULL GENOTYPES IN GENERAL POPULATION GSTM1 GSTT1 Asmundo et al. 54.67% 24.67% Griffiths et al. 36% 8% Ada et al. 51.9% 17.3% Uhm et al. 51.4% 52.6%
  • 5.
    • The GSTM1 and GSTT1 “null” genotypes are linked to skin cancers, psoriasis, allergic dermatoses
    GLUTATHIONE S-TRANSFERASE
    • Enzymes for detoxification of electrophyle compounds by conjugation with glucuronates
    • Frequent genetic polymorphism
    • Main groups of polymorphisms: GSTA, GSTM, GSTP, GSTT
    • The “null” genotype of GSTM1 and GSTT1 can be found in a significant part of the general population
  • 6.
    • Uhm YK, Yoon SH, Kang IJ, Chung JH, Yim SV, Lee MH. Association of glutathione S-transferase gene polymorphisms (GSTM1 and GSTT1) of vitiligo in Korean population. Life Sci. 2007; 81 (3): 223-7.
    • Liu L, Li C, Gao J, Li K, Gao L, Gao T. Genetic polymorphisms of glutathione S-transferase and risk of vitiligo in the Chinese population. J Invest Dermatol. 2009; 129 (11): 2646-52.
    GLUTATHIONE S-TRANSFERASES AND VITILIGO
  • 7. AIM OF THE STUDY To define the possible role of the GSTM1 and/or GSTT1 “null” genotype as a risk factor for the development of vitiligo in a population of patients from a Mediterranean area (Sicily and Calabria)
  • 8. MATERIALS AND METHODS
    • Study population: 58 consecutive vitiligo patients (28 M, 30 F; mean age 25.22 ± 11.37 years), all Caucasian, born and living in Sicily or Calabria
    • Control population: 150 healthy subjects, with a similar age and sex distribution
    • Cell sample obtained by buccal swab
    • GSTM1 and GSTT1 genotyping
  • 9. GSTM1 AND GSTT1 GENOTYPING
    • Extraction by “Chelex ® 100” method
    • PCR amplification
    • Electrophoresis of PCR products on ultrathin polyacrylamide gel
    • Silver staining
    • Bands of interest: - 480 bp (GSTT1) - 215 bp (GSTM1)
    • Internal control: beta-globin gene
  • 10. MATERIALS AND METHODS
    • Study population: 58 consecutive vitiligo patients (28 M, 30 F; mean age 25.22 ± 11.37 years), all Caucasian, born and living in Sicily or Calabria
    • Control population: 150 healthy subjects, with a similar age and sex distribution
    • Cell sample obtained by buccal swab
    • GSTM1 and GSTT1 genotyping
    • Statistical analysis: Chi square test (significant if p<0.05)
  • 11. RESULTS Genotype GSTM1 Null Active Patients 35 23 Controls 82 68 p = 0.459 GSTT1 Null Active Patients 22 36 Controls 19 113 p = 0.057
  • 12. RESULTS GSTM1 GSTT1 Patients Controls active active 15 49 active null 8 19 p = 0.535 null active 21 64 p = 0.858 null null 14 18 p = 0.041
  • 13. ASSOCIATION BETWEEN THE “NULL” GST GENOTYPE AND VITILIGO
    • Uhm YK et al., Life Sci . 2007 Vitiligo associated with GSTM1 null and GSTM1/GSTT1 “double null”
    • Liu L et al., J Invest Dermatol. 2009 Vitiligo associated with GSTT1 null and GSTM1/GSTT1 “double null”
    • Present study Vitiligo associated with GSTM1/GSTT1 “double null”
  • 14. Autoimmune Toxic Neurogenic VITILIGO: PATHOGENIC HYPOTHESES
  • 15. Kostyuk VA et al., Antioxid Redox Signal 2010 We found significantly suppressed mRNA and protein expression of GST M1 isoform, and higher-than-normal levels of both 4-hydroxy-2-nonenal (HNE)-protein adducts and H 2 O 2 in the cultures of keratinocytes derived from unaffected and affected skin of vitiligo patients The broad spectrum of major cytokines, chemokines, and growth factors was dysregulated in both blood plasma and cultured keratinocytes of vitiligo patients Exogenous HNE added to normal keratinocytes induced a vitiligo-like cytokine pattern, and H 2 O 2 overproduction accompanied by adaptive upregulation of catalase and GSTM1 genes
  • 16. DIFFERENT GSTM1/T1 GENOTYPES IN VITILIGO PATIENTS: POSSIBLE EXPLANATIONS
    • Different “gene pool”
    • Variable importance of GST M1 and T1 in the “setup” of antioxidant mechanisms in different populations
    • Environmental conditions
    • Life style
  • 17. FUTURE PERSPECTIVES
    • GST genotyping of various populations
    • Further studies on association between GST polymorphisms and vitiligo
    • Exact definition of the role of GSTs in the pathogenic mechanisms of vitiligo
  • 18. OUR NEW PROJECT
    • Simultaneous definition of the genotype of all possibly pathogenically relevant antioxidant enzymes
    • Correlation between each genotype and vitiligo
    • Calculation of the “antioxidant potential” of a subject and the individual contribution of each enzyme to it
    • Definition of individual disease risk and possible preventive measures
    • Study of connections among autoimmune, oxidative and neural mechanisms