GLUTATHIONE-S-TRANSFERASE GENE POLYMORPHISM AS A RISK FACTOR IN CHILDREN WITH BRONCHIAL ASTHMA

Yıl 2025, Cilt: 5 Sayı: 13, 83 - 90, 11.06.2025

Murat Ekinci , Murat Elevli , Abdurrahman Özdemir

https://doi.org/10.54270/atljm.2025.84

Öz

Aim: This study aimed to investigate whether glutathione-S-transferase gene polymorphism is a risk factor in children with bronchial asthma and whether it could serve as a marker for diagnosis.
Materials and Methods: Our study was conducted between May 2004 and May 2005 on patients diagnosed with asthma who presented with respiratory symptoms at the Pediatrics Clinic. The patients were staged according to the GINA criteria and were compared based on age, gender, age of symptom onset, passive smoking, hospital admissions, and atopy. All patients underwent hemogram, sedimentation, PPD, chest X-ray, sinus X-ray, nasal eosinophilia, IgG, A, M, E, skin, sweat, and pulmonary function tests. For the analysis of GSTM1 and GSTT1 genes, the multiplex Polymerase Chain Reaction (PCR) method was used; for the study of Cytochrome P4501A1 gene Msp1 polymorphism, the PCR-Restriction Fragment Length Polymorphism (RFLP) method was employed.
Results: Our study was conducted with 105 patients aged 1-15 years and a control group of 30 individuals. There were 38 (36.2%) patients with intermittent asthma, 28 (26.7%) with mild persistent asthma, 28 (26.7%) with moderate persistent asthma, and 11 (10.5%) with severe persistent asthma. The average age was 7.36±2.9, with a gender distribution of 51 females and 54 males. The average age of symptom onset was 3.95±3.1 years. A significant relationship was found between disease severity and the prevalence of atopy (p<0.05). No significant difference was found in gene polymorphism between the asthma patients and the control group (p>0.05). When comparing the mild and severe asthma groups for glutathione-S-transferase gene polymorphism, a statistically significant difference was found in GSTM1 carrier status (p<0.05).
Conclusion: Although it is still difficult to fully explain the exact role of GST genes in the pathogenesis of bronchial asthma, the results obtained suggest that there is a relationship between the severity of asthma and the presence of GSTM1 gene deletion.

Anahtar Kelimeler

Asthma, Children, Glutathione transferase

Etik Beyan

There is no conflict of interest.

BRONŞİYAL ASTIMLI ÇOCUKLARDA RİSK FAKTÖRÜ OLARAK GLUTATYON-S-TRANSFERAZ GEN POLİMORFİZMİ

Öz

Amaç: Bu çalışmada bronşiyal astımlı çocuklarda glutatyon-s-transferaz gen polirnorfizminin bir risk faktörü olup olmadığını ve tanı için bir marker olup olamayacağını araştırdık.
Gereç ve Yöntemler: Çalışmamız Mayıs 2004-Mayıs 2005 tarihleri arasında Çocuk Sağlığı ve Hastalıkları Polikliniği'ne solunum semptomları ile gelen astım tanısı konulmuş hastalarda gerçekleştirildi. Hastalar GINA kriterlerine göre evrelendirilerek kendi aralarında yaş, cinsiyet, semptomların başlangıç yaşı, pasif sigara içiciliği, hastane yatışı ve atopi yönünden karşılaştırıldı. Bütün hastalara hemogram, sedimentasyon, ppd, akciğer grafisi, sinüs grafisi, nazal eosinofili, Ig G, A, M, E, deri testleri, ter testleri, solunum fonksiyon testleri yapıldı. GST-mü-1 ve GST-tehta1 genlerinin analizi için multipleks Polymerase Chain Reaction(PCR) yöntemi; Sitokrom P 4501A1 geni Mspl polimorfiziminin analizi için PCR-Restriction Fragment Length Polymorphism (RFLP) yöntemi kullanıldı.
Bulgular: Çalışmamız yaşları 1-15 yaş arasında değişen 105 hasta ve 30 kontrol grubu ile gerçekleştirildi. İntermittan 38 (%36,2), hafif persistan 28 (%26,7), orta persistan 28 (%26,7), ağır persistan 11 (%10,5) astımlı hasta vardı. Yaş ortalaması 7,36±2,9; cinsiyet dağılımı kız/erkek: 51/54; semptomların başlangıç yaşı ortalama 3,95±3,1 yıldı. Hastalığın şiddeti ile atopi görülme oranı arasında anlamlı bir ilişki saptandı (p<0,05). Astım hastaları ile kontrol gurubu arasında gen polimorfizmi açısından anlamlı fark tespit edilmedi (p>0,05). Hafif ve ağır astım grupları kendi aralarında glutatyon-s-transferaz gen polimorfizmi açısından karşılaştırıldıklarında GSTM 1 taşıyıcılığı açısından istatistiksel olarak anlamlı bir farklılık mevcuttu (p<0,05).
Sonuç: GST genlerinin bronşiyal astım patogenezindeki tam rolünü açıklamak henüz çok zor olsa da elde edilen sonuçlar astımın şiddetiyle GSTM1 gen delesyonu varlığı arasında bir ilişki olduğunu göstermektedir.

Anahtar Kelimeler

Astım, Çocuklar, Glutatyon transferaz

Etik Beyan

Çıkar çatısması yoktur.

Kaynakça

• Baterman ED, Barnes PJ, Bousquet J, et al. Definition of asthma. Global strategy for asthma management and prevention 2005 (GINA-2005); 1:2.
• Mortimer K, Lesosky M, García-Marcos L, et al. The burden of asthma, hay fever and eczema in adults in 17 countries: GAN Phase I study. Eur Respir J. 2022;60(3):2102865.
• Neyzi O, Ertuğrul T. Pediatri. 3.Baski. İstanbul: Nobel Tıp Kitabevleri Ltd. Şti, 2002: 616-17.
• Jesenak M, Zelieskova M, Babusikova E. Oxidative Stress and Bronchial Asthma in Children-Causes or Consequences? Front Pediatr. 2017;5:162.
• Rahman I, Mulier B, Gilmour PS, et al. Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappa B. Biochem Pharmacol. 2001;62(6):787-94.
• Portelli MA, Hodge E, Sayers I. Genetic risk factors for the development of allergic disease identified by genome-wide association. Clin Exp Allergy. 2015;45(1):21-31.
• Lima CS, Néri IA, Lourenço GJ, et al. Glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genetic polymorphisms and atopic asthma in children from Southeastern Brazil. Genet Mol Biol. 2010;33(3):438-41.
• Gilliland FD, Gauderman WJ, Vora H, et al. Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth. Am J Respir Crit Care Med. 2002;166(5):710-16.
• Sambrook J, Russell DW. “MolecularCloning: A Laboratory Manual.” Cold Spring HarborLaboratoryPress (2001).
• Ausubel FM, Brent R, Kingston RE, et al. “CurrentProtocols in MolecularBiology.” John Wiley&Sons, Inc. (1999).
• Saiki RK et al. “Primer-directedenzymaticamplification of DNA with a thermostable DNA polymerase.” Science (1988).
• Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351(9111):1225-32.
• The Collaborative Study on the Genetics of Asthma. A genome-wide search for asthma susceptibility loci in ethnically diverse populations: The Collaborative Study on the Genetics of Asthma (CSGA). Nat Genet 1997;15:389-92.
• Bleecker ER. Postma DS, Meyers DA. Evidence for multiple genetic susceptibility loci for asthma. Am J Respir Crit Care Med 1997; 156:113-16.
• Nicolaides NC, Holroyd KJ, Ewart SL, et al. Interleukin 9: a candidate gene for asthma. Proc Natl Acad Sci U S A. 1997;94(24):13175-80.
• Greene LS. Asthma and oxidant stress: nutritional, environmental, and genetic risk factors. J Am Coll Nutr. 1995;14(4):317-24.
• Oyama T, Mitsudomi T, Kawamoto T, et al. Detection of CYP1A1 gene polymorphism using designed RFLP and distributions of CYP1A1 genotypes in Japanese. Int Arch Occup Environ Health. 1995;67(4):253-56.
• Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000;61(3):154-66.
• Strange RC, Spiteri MA, Ramachandran S, et al. Glutathione-S-transferase family of enzymes. Mutat Res. 2001;482(1-2):21-6.
• Hayes JD, Strange RC. Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress. Free Radic Res. 1995;22(3):193-207.
• Eaton DL. Biotransformation enzyme polymorphism and pesticide susceptibility. Neurotoxicology. 2000;21(1-2):101-11.
• Barnes PJ. Reactive oxygen species and airway inflammation. FreeRadicBiolMed. 1990;9(3):235-43.
• Brasch-Andersen C, Christiansen L, Tan Q, et al. Possible gene dosage effect of glutathione-S-transferases on atopic asthma: usingreal-time PCR for quantification of GSTM1 and GSTT1 gene copy numbers. Hum Mutat. 2004;24(3):208-14.
• Scott WK, Pericak-Vance MA, Haines JL. Genetic analysis of complex diseases. Science. 1997;275(5304):1327-30.
• Strange RC, Fryer AA. The glutathione S-transferases: influence of polymorphism on cancersusceptibility. IARC SciPubl. 1999;(148):231-49.
• Habig WH, Jakoby WB. Glutathione S-transferases (ratandhuman). Methods Enzymol. 1981;77:218-31.
• Lee YL, Lin YC, Hsiue TR, et al. Indoor and outdoor environmental exposures, parentalatopy, andphysician-diagnosedasthma in Taiwanese school children. Pediatrics. 2003;112(5):e389.
• Weiss ST, Tager IB, Muñoz A, et al. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis. 1985;131(4):573-78.
• Chilmonczyk BA, Salmun LM, Megathlin KN, et al. Association between exposure to environmental tobacco smoke and exacerbations of asthma in children. N Engl J Med. 1993;328(23):1665-69.
• Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ. 1996;312(7040):1195-99.
• Kulig M, Bergmann R, Tacke U, et al. Long-lasting sensitization to food during the first two years precedes allergic airway disease. The MAS Study Group, Germany. Pediatr Allergy Immunol. 1998;9(2):61-7.
• Pearce N, Pekkanen J, Beasley R. How muchasthma is reallyattributableto atopy? Thorax. 1999;54(3):268-72.
• Baterman ED, Barnes PJ, Bousquet J, et al. Definition of asthma. Global strategy for asthma management and prevention 2005(GINA-2005); 5:74-76.
• Özkan Karaman. Bronşiyal Astım Tedavisinde Yenilikler. 38. Türk Pediatri Kongresi Kitabı 2002:186.
• Ivaschenko TE, Sideleva OG, Baranov VS. Glutathione- S-transferase micro and theta gene polymorphisms as new risk factors of atopic bronchial asthma. J Mol Med (Berl). 2002;80(1):39-43.
• Fryer AA, Hume R, Strange RC. The development of glutathione S-transferase and glutathione peroxidase activities in human lung. Biochim Biophys Acta 1986; 883:448-53.
• Spiteri MA, Bianco A, Strange RC, et al. Polymorphisms at the glutathione S-transferase, GSTP1 locus: a novel mechanism for susceptibility and development of atopic airway inflammation. Allergy. 2000;55 Suppl 61:15-20.
• Gilliland FD, Rappaport EB, Berhane K, et al. Effects of glutathione S-transferase P1, M1, and T1 on acute respiratory illness in school children. Am J Respir Crit Care Med. 2002;166(3):346-51.
• Romieu I, Sienra-Monge JJ, Ramírez-Aguilar M, et al. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City. Thorax. 2004;59(1):8-10.
• Gilliland FD, Li YF, Dubeau L, et al. Effects of glutathione S-transferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children. Am J Respir Crit Care Med. 2002;166(4):457-63.
• Karam RA, Pasha HF, El-Shal AS, et al. Impact of glutathione-S-transferase gene polymorphisms on enzyme activity, lung function and bronchial asthma susceptibility in Egyptian children. Gene. 2012 Apr 15;497(2):314-9. doi: 10.1016/j.gene.2012.01.059. Epub 2012 Feb 1. PMID: 22326267.
• El Rifai N, Moustafa N, Degheidy N, et al. Glutathione S transferase theta1 and mu1 gene polymorphisms and phenotypic expression of asthma in Egyptian children: a case-control study. Ital J Pediatr. 2014;40(1):22. Published 2014 Feb 21. doi:10.1186/1824-7288-40-22
• StepanovaYeI, KolpakovYeI, VdovenkoVYu, et al. Role of genetic predisposition, gene polymorphism of glutathione S-transferase (GSTT1, GSTM1, GSTP1), and some adverse factors in the development of bronchial asthma in children - residents of radioactively contaminated areas. Problems of Radiation Medicine and Radiobiology. 2021;26:449–463.
• Kumar A, Ahmed T, Parvez MK, at al. Glutathione S-transferase gene polymorphism and asthma: a case-control study in a pediatric population. Pharmacogenomics. 2022;23(7):405-413. doi:10.2217/pgs-2022-0017
• Su X, Ren Y, Li M, at al. Association of glutathione S-transferase M1 and T1 genotypes with asthma: A meta-analysis. Medicine (Baltimore). 2020;99(34):e21732.