Alokananda Chakraborty, Priyanka Pallapolu, Seelamneni Thulasamma, Lahari Kuna, Shravan Kumar Ghali, Kaiser Jamil, Ghazala Javed, Munawwar Husain Kazmi
Alokananda Chakraborty1*, Priyanka Pallapolu1, Seelamneni Thulasamma1, Lahari Kuna1, Shravan Kumar Ghali1, Kaiser Jamil2, Ghazala Javed3, Munawwar Husain Kazmi1
1BCMB Laboratory, National Research Institute of Unani Medicine for Skin Disorders, ESI x Road, Hyderabad, Telangana, India.
2Bhagwan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, Hyderabad - 500004, Telangana, India.
3Central Council for Research in Unani Medicine (CCRUM), New Delhi, India.
Volume - 15,
Issue - 5,
Year - 2022
Background: Generalized vitiligo is a common, multifaceted, polygenic condition in which autoimmune loss of melanocytes results in depigmented skin patches, overlying hair and mucous membranes. NLRP1 has been proposed to be implicated in the susceptibility of a broad variety of autoimmune disorders, including generalized vitiligo (GV). Genetic polymorphisms in the NLRP1 encoding gene (formerly known as NALP1) have previously been found to be linked with GV and there is uncertainty as to their role in the modulation of NLRP1 expression. Oxidative stress is a significant pathogenesis theory for vitiligo. Glutathione S-transferases (GSTs) are enzymes active in the defense of cells against chemical toxicity and stress.This study validates some of the Unani concepts of humors or temperaments (Phenotypes), with regard to Vitiligo, Where vitiligo is regarded as a phlegmatic disease. We selected Vitiligo subjects with Phlegmatic Clinical Phenotype for our study, with an aim to determine its association with the genetic biomarkers- NLRP1, GSTM1 and GSTT1 null genotypes and other biochemical parameters. Methods: The Unani clinicians randomly selected 100 vitiligo patients with a phlegmatic Clinical Phenotype who were attending NRIUMSD for treatment and 100 healthy volunteers belonging to Phlegmatic (Phlegmatic clinical Phenotype). Besides looking at temperaments/ humors as susceptibility factors – we included a genetic factor- NLRP1, GSTM1- and GSTT1-null genotypes to our investigation. We have genotyped the NLRP1, GSTM1- and GSTT1-null genotypes by PCR-RFLP and by Multiplex PCR, GST protein level estimation by ELISA method. Results: NLRP1 rs2670660 polymorphism was shown to be in significant association with GV, with the presence of minor alleles in active GV. We found that the frequencies of GSTM1 null genotype and GSTT1 null genotype in vitiligo patients were significantly high compared to the controls (OR= 1.47, 95% CI=0.765--2.861), (OR = 4.75, 95% CI = 2.131-10.63), respectively. In combination analysis with both genes, the results suggested significant association of vitiligo risk with both GSTM1\GSTT1 null genotypes (OR=4.83, 95% CI=1.523– 15.32).We observed a significant decrease (p<0.001) in GST protein levels. Conclusion: Our findings indicate that NLRP1 rs2670660 polymorphism may be genetic risk factor for susceptibility to GV and the null genotypes of GSTM1 and GSTT1 of both genes increase the risk of the disease. A significant decrease (p<0.001) in GST protein levels appeared to be a key feature in Vitiligo subjects, Therefore, detection of antioxidant enzyme levels can be effective biomarkers for early detection of the disease. We believed that GSTM1-and GSTT1-null genotype polymorphisms were associated with an increased risk of vitiligo. This is the first study of its kind along with Clinical Phenotype as per Unani Philosophy.
Cite this article:
Alokananda Chakraborty, Priyanka Pallapolu, Seelamneni Thulasamma, Lahari Kuna, Shravan Kumar Ghali, Kaiser Jamil, Ghazala Javed, Munawwar Husain Kazmi. Genetic variations in NLRP1 and Glutathione S-Transferase are associated with Generalized Vitiligo of Phlegmatic Clinical Phenotypes in Unani Medicine Philosophy of South Indian Population. Research Journal of Pharmacy and Technology. 2022; 15(5):2221-7. doi: 10.52711/0974-360X.2022.00369
Alokananda Chakraborty, Priyanka Pallapolu, Seelamneni Thulasamma, Lahari Kuna, Shravan Kumar Ghali, Kaiser Jamil, Ghazala Javed, Munawwar Husain Kazmi. Genetic variations in NLRP1 and Glutathione S-Transferase are associated with Generalized Vitiligo of Phlegmatic Clinical Phenotypes in Unani Medicine Philosophy of South Indian Population. Research Journal of Pharmacy and Technology. 2022; 15(5):2221-7. doi: 10.52711/0974-360X.2022.00369 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2022-15-5-51
1. Azmi-Ahmad Altaf: Basic concepts of Unani medicine a-critical study.
2. Hameed Abdul H.K. “A Temperament and Medicine” International Congress of Orientalists, Paris, 1973.
3. Nafis Burhan-al-din, Kulyat-e-Nafisi Vol.2, Daftar-alMasihi, Delhi, 1935.
4. R. Vinodini, A. M. Amala Hazel, M. Meenakshi Sundaram, N. J. Muthukumar. Clinical Evaluation of Parangipattai chooranam (internal) and Annabedhi chenduram (external) for Venpulli (Vitiligo) in children. Research J. Pharm. and Tech. 2019; 12(12): 5932-5936. doi: 10.5958/0974-360X.2019.01029.1.
5. Hameed Abdul and Vohra, S.B. Is Human Body A Microcosm Paper presented at international Conference, New Delhi, 1987.
6. Grimes P, Nordlund JJ, Pandya AG, Taylor S, Rendon M, Ortonne JP. J Am Acad Dermatol. Increasing our understanding of pigmentary disorders. 2006 May;54 (5 Suppl 2):S255-61.
7. Howitz J, Brodhagen H, Schwartz M, Thomsen K. Prevalence of vitiligo. Arch Dermatol 1977; 113:47-52.
8. Kemp, EH. Waterman, EA.,Weetman, AP. Autoimmune aspects of vitiligo. Autoimmunity; 2001; 34: 65-77, doi:10.3109/08916930108994127.
9. Rezaei, N., Gavalas, NG., Weetman, AP., Kemp, EH.Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol; 2007; 21: 865-876, doi: 10.1111/ j.1468-3083.2007.02228.x.
10. Spritz, RA. The genetics of generalized vitiligo and associated autoimmune diseases. Pigment Cell Res; 2007; 20:271-278, doi: 10.1111/j.1600-0749.2007.00384.x.
11. Shajil, EM., Chatterjee, S., Agrawal, D., Bagchi, T., Begum, R, Vitiligo: pathomechanisms and genetic polymorphism of susceptible genes.; Indian J ExpBiol; 2006, 44: 526-539.
12. Ingordo, V., Gentile, C., Iannazzone, SS., Cusano, F., Naldi, L Vitiligo and autoimmunity: an epidemiological study in a representative sample of young Italian males J Eur Acad Dermatol Venereol. 2011; 25: 105-109, doi: 10.1111/j.1468-3083.2010.03696.x.
13. Jin Y, Birlea SA, Fain PR et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet 2012; 44:676–80.
14. Ting JP, Willingham SB, Bergstralh DT. NLRs at the intersection of cell death and immunity. Nat Rev Immunol 2008; 8:372–9.
15. Jin Y, Mailloux CM, Gowan K et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007; 356:1216–25.
16. Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1 beta in inflammatory disorders. Nat Clin Pract Rheumatol 2008; 4:34–42.
17. Ting JP, Davis BK. Caterpiller: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 2005; 23:387–414.
18. Jin Y, Birlea SA, Fain PR et al. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Invest Dermatol 2007; 127:2558–62.
19. Alkhateeb A, Qarqaz F. Genetic association of NALP1 with generalized vitiligo in Jordanian Arabs. Arch Dermatol Res 2010; 302:631–4.
20. Gregersen PK. Modern genetics, ancient defences, and potential therapies. N Engl J Med. 2007;356(12):1263–6. Epub pmid:17377166
21. Kummer JA, Broeckhuizen R, Everett H et al. Inflammasome components NALP1 and 3 show distinct but separate expression pro- files in human tissues, suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 2007; 55:443–52.
22. Faustian B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, RouillerI, Reed JC. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Molecular Cell, 2007, 25(5):713-24
23. Bickers DR, Athar M . Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol; 2006, 126:2565–75.
24. Dell’Anna ML, Ottaviani M, Albanesi V, Vidolin AP, Leone G, Ferraro C et al. Membrane lipid alterations as a possible basis for melanocyte degeneration in vitiligo. J Invest Dermatol, 2007; 127:1226–33.
25. Passi S, Grandinetti M, Maggio F, Stancato A, De Luca C . Epidermal oxidative stress in vitiligo. Pigment Cell Res 1998,11:81–5.
26. Sneha James, Krishnan Namboori P K, Leena K Pappachen. Glutathione Derivatives as Potential Drugs for Colorectal Cancer Resulted by APC Mutations. . Research J. Pharm. and Tech, 2019 , 12 (8) : 3911-3914. doi: 10.5958/0974-360X.2019.00673.5.
27. Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinaserelated protein in vitiligo. Br J Dermatol 2001;144:55–65.
28. Tulsi Rani Thakre, Abha Singh, Mitashree Mitra. Investigation on Glutathione-S-transferase M1 and T1 gene polymorphisms as risk factor in Cervical Cancer. Research J. Pharm. and Tech 2016; 9(12):2295-2300. doi: 10.5958/0974-360X.2016.00462.5.
29. Koca R, Armutcu F, Altinyazar HC, Gurel A . Oxidant-antioxidant enzymes and lipid peroxidation in generalized vitiligo. Clin Exp Dermatol 2004; 29:406–9.
30. Ines D, Sonia B, Riadh BM, Amel el G, Slaheddine M, Hamida T et al. A comparative study of oxidant-antioxidant status in stable and active vitiligo patients. Arch Dermatol Res, 2006; 298:147–52.
31. Shiv Kumar Patel, Moumita Sinha, Mitashree Mitra. Glutathione-S-transferase M1 and T1 gene Polymorphism as Risk Factors of Oral Squamous Cell Carcinoma: A Preliminary Investigation. Research J. Pharm. and Tech. 2012; 5(7): Page 918-920.
32. Arican O, Kurutas EB . Oxidative stress in the blood of patients with active localized vitiligo. Acta Dermatovenerol Alp Panonica Adriat, 2008,17:12–6.
33. Huda Kadhem Mohseen, Baydaa Taher Sih, Sura Salah Al-Saidi. Effect of the (ɣ-ray) and Laser Radiation on the Important Antioxidant Enzyme Glutathione(GSH) level in Serum. Research J. Pharm. and Tech 2017; 10(10):3386-3390. doi: 10.5958/0974-360X.2017.00602.3.
34. Xiao Z, Yang L, Xu Z, Zhang Y, Liu L, Nie L et al. Glutathione S-transferases (GSTT1 and GSTM1) genes polymorphisms and the treatment response and prognosis in Chinese patients with de novo acute myeloid leukemia. Leuk Res,2008; 32:1288–91.
35. Martinon F, Tschopp J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol 2005; 26:447–54.
36. Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003; 4:95–104.
37. Huang CL, Nordlund JJ, Boissy R. Vitiligo: a manifestation of apoptosis. Am J Clin Dermatol 2002; 3:301–8.
38. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10:417–26.
39. Van de Veerdonk FL, Netea MG, Dinarello CA, Joosten LA. Inflammasome activation and IL-1b and IL-18 processing during infection. Trends Immunol 2011; 32:110–16.
40. Taieb A. NALP1 and the inflammasomes: challenging our perception of vitiligo and vitiligo-related autoimmune disorders. Pigment Cell Res 2007; 20:260–2.
41. Kerb R, Brockmoller J, Reum T, Roots I. Deficiency of glutathione S-transferases T1 and M1 as heritable factors of increased cutaneous UV sensitivity. J Invest Dermatol, 1997; 108:229–32
42. Vavilin VA, Safronova OG, Lyapunova AA, Lyakhovich VV, Kaznacheeva LF, Manankin NA et al. Interaction of GSTM1, GSTT1, and GSTP1 genotypes in determination of predisposition to atopic dermatitis. Bull Exp Biol Med, 2003; 136:388–91
43. Liu, L., Li, C., Gao, J., Li, K., Gao, L., Gao, T. Genetic polymorphisms of glutathione S-transferase and risk of vitiligo in the Chinase population. J. Invest Dermatol., 2009, 129: 2646-2652.
44. Abd Rabou, F., Elserogy, H., Gheida, S., EL-Ashmawy, A. Glutathione S-Transferase Gene Polymorphisms (GSTM1 and GSTT1) in Vitiligo Patients. Life Sci J 2011; 8(4): 785-792.