EVALUATION OF GLUTATHIONE-S-TRANSFERASE P1 POLYMORPHISM AND ITS RELATION TO BONE MINERAL DENSITY IN EGYPTIAN CHILDREN AND ADOLESCENTS WITH BETA- THALASSEMIA MAJOR
Main Article Content
Keywords
GSTP1 polymorphism, osteoporosis, thalassemia
Abstract
Background:Osteoporosis is a major problem in beta thalassemia major (TM) patients. Increased oxidative stress and its controlling genes were linked to osteoporosis. Glutathione S-transferase P1 (GSTP1),Ile105 Val variant is a functional mutation with reduced ant-oxidative property .No data are available about this variant or its association with osteoporosis among thalassemia patients yet. Objectives: The aim of this study was to investigate Ile105Val polymorphism and its possible association with bone mineral density (BMD) values in a group of TM children. Methods:Thirty five TM patients and 30 age and sex matched healthy controls were included. Liver and renal functions, serum ferritin, calcium, phosphorous, alkaline phosphatase and osteocalcin were assayed. BMD was determined by DXA with calculation of Z-scores at lumbar spine (Ls) and femoral neck (Fn).Height for age z- score (HAZ) adjusted BMD Z-scores were considered . GSTP1 Ile105Val polymorphism was studied by polymerase chain reaction-restriction fragment length polymorphism. Results:The relative frequency of 105 Val allele was significantly higher in TM patients than the controls (P<0.0001). Significant association between genotype subgroups and BMD parameters was detected. Mutant homozygotes had significant lower BMD , Z –score and haz -adjusted BMD Z-score at both Ls and Fn compared to wild homozygotes ( Ps =0.029, 0.008, 0.011, 0.001,0.02, 0.001) with significant higher osteocalcin level compared to heterozygotes and wild homozygotes (P=0.012 and P=0.013,respectively). Conclusion: The results indicated that 105Val allele was frequent among TM patients and could increase their susceptibility to osteoporosis. Large sample studies are required to confirm these findings.
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References
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29. Chen JT, Hosoda K, Hasumi K, Ogata E, Shiraki M .Serum N-terminal osteocalcin is a good indicator for estimating responders to hormone replacement therapy in postmenopausal women. J Bone Miner Res.1996; 11:1784-1792.
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31. Mlakar SJ, Prezelj J, Marc J.Testing GSTP1 genotypes and haplotypes interactions in Slovenian post-/pre-menopausal women: novel involvement of glutathione S-transferases in bone remodeling process. Maturitas .2012; 71(2):180-187.
32. Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J .Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem .1997;272(15):10004–10012.
33. Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL .Increased lipid oxidation causes oxidative stress, increased PPAR{gamma} expression and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem .2009; 284:27438–27448.
34. Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ .Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappa B. Biochem Biophys Res Commun .2004; 314(1):197-207.
35. Hoensch H, Morgenstern I, Petereit G, Siepmann M, Peters WH, Roelofs HM, Kirch W .Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system. Gut .2002; 50(2):235-240.
36. Vasieva O .The many faces of glutathione transferase pi. Curr Mol Med .2011; 11(2):129-139.
37. Yin Z, Ivanov VN, Habelhah H, Tew K, Ronai Z .Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res .2000; 60(15):4053-4057.
38. Trost Z, Trebse R, Prezelj J, Komadina R, Logar DB, Marc J . A microarray based identification of osteoporosis-related genes in primary culture of human osteoblasts . Bone .2010; 46(1):72-80.
39. Yamaguchi J, Hasegawa Y, Kawasaki M, Masui T, Kanoh T, Ishiguro N, Hamajima N .ALDH2 polymorphisms and bone mineral density in an elderly Japanese population. Osteoporos Int .2006; 17(6):908-913.
40. Miller DP, Neuberg D, de Vivo I, Wain JC, Lynch TJ, Su L, Christiani DC .Smoking and the risk of lung cancer: susceptibility with GSTP1 polymorphisms. Epidemiology .2003; 14(5):545-551.
41. Park JH, El-Sohemy A, Cornelis MC, Kim HA, Kim SY, Bae SC .Glutathione S-transferase M1, T1, and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis. Rheumatol Int .2004;24(3):157-163 .
42. Palmer CN, Young V, Ho M, Doney A, Belch JJ. Association of common variation in glutathione S-transferase genes with premature development of cardiovascular disease in patients with systemic sclerosis. Arthritis Rheum .2003;48:854–855 .
43. Hayes JD, Flanagan JU, Jowsey IR.Glutathione transferases. Annu Rev Pharmacol Toxicol .2005; 45: 51-88.
44. Ghone RA, Kumbar KM, Suryakar AN, Katkam RV, Joshi NG .Oxidative stress and disturbance in antioxidant balance in beta thalassemia major. Indian J Clin Biochem .2008; 23(4):337-340.
45. Wu KH, Chang JG, Ho YJ, Wu SF, Peng CT. Glutathione S-transferase M1 gene polymorphisms are associated with cardiac iron deposition in patients with beta-thalassemia major. Hemoglobin .2006; 30(2):251-256.
46. Origa R, Satta S, Matta G, Galanello R.Glutathione S-transferase gene polymorphism and cardiac iron overload in thalassaemia major. Br J Haematol.2008; 142(1):143-145.
47. Daar S, Pathare AV, Jain R, Zadjali SA, Pennell DJ .T2* cardiovascular magnetic resonance in the management of thalassemia patients in Oman. Haematologica .2009; 94(1):140-141.
48. Sharma V, Kumar B, Saxena R. Glutathione S-transferase gene deletions and their effect on iron status in HbE/beta thalassemia patients .Ann Hematol .2010; 89(4):411-414.
49. Zhao L, Wang Y, Wang Z, Xu Z, Zhang Q4, Yin M . Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character. J Nutr Biochem .2015;Jun 16. pii: S0955-2863(15) 00142-00144.
2. Haidar R, Musallam KM, Taher AT .Bone disease and skeletal complications in patients with ? thalassemia major. Bone .2011;48(3):425-432.
3. Voskaridou E, Terpos E .New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol.2004; 127: 127–139.
4. NIH Consens Statement .Osteoporosis prevention, diagnosis, and therapy, NIH Consens Statement 2000; 17(1):1-45.
5. Basu S, Michaëlsson K, Olofsson H, Johansson S, Melhus H .Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun. 2001; 288(1):275-279.
6. Lee YJ, Hong JY, Kim SC, Joo JK, Na YJ .The association between oxidative stress and bone mineral density according to menopausal status of Korean women. Obstet Gynecol Sci .2015; 58(1):46-52.
7. Kuyumcu ME, Yesil Y, Oztürk ZA, C?nar E, K?z?larslanoglu C, Halil M, Ulger Z, Yesil NK, Cankurtaran M, Ar?o?ul S .The association between homocysteine (hcy) and serum natural antioxidants in elderly bone mineral densitometry (BMD). Arch Gerontol Geriatr .2012; 55:739–743.
8. Sontakke AN, Tare RS . A duality in the roles of reactive oxygen species with respect to bone metabolism. Clin Chim Acta .2002; 318(1-2):145-148.
9. Nebert DW, Vasiliou V. Analysis of the glutathione S-transferase (GST) gene family. Hum Genomics .2004; 1 :460–464.
10. Tew KD . Glutathione -associated enzymes in anticancer drug resistance. Cancer Res .1994; 54(16):4313-4320.
11. Henderson CJ, McLaren AW, Moffat GJ, Bacon EJ, Wolf CR. Pi-class glutathione S-transferase: regulation and function. Chem Biol Interact .1998;111-112:69-82.
12. Ntais C, Polycarpou A, Ioannidis JP . Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev.2005; 14(1):176-181.
13. Carbonell Sala S, Masi L, Marini F, Del Monte F, Falchetti A, Franceschelli F, Brandi ML.Genetics and pharmacogenetics of osteoporosis. J Endocrinol Invest .2005; 28(10 Suppl) :2-7.
14. Mlakar SJ, Osredkar J, Prezelj J, Marc J.The antioxidant enzyme GPX1 gene polymorphisms are associated with low BMD and increased bone turnover markers. Dis Markers .2010;29(2):71–80.
15. Mlakar SJ, Osredkar J, Prezelj J, Marc J .Antioxidant enzymes GSR, SOD1,SOD2 and CAT gene variants and BMD values in postmenopausal women: a genetic association analysis. Menopause .2011;19.3:1–9.
16. Mlakar SJ, Osredkar J, Prezelj J, Marc J .Opposite effects of GSTM1-and GSTT1-gene deletion variants on bone mineral density. Dis Markers .2011;31(5):279–287.
17. Oh B, Kim SY, Kim DJ, Lee JY, Lee JK, Kimm K, Park BL, Shin HD, Kim TH, Park EK, Koh JM, Kim GS. Associations of catalase gene polymorphisms with bone mineral density and bone turnover markers in postmenopausal women. J Med Genet .2007; 44(1):e62.
18. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL. CDC growth charts: United States.
Adv Data .2000; 314:1-27.
19. Tanner JM .Growth at Adolescence. 2nd ed. Oxford UK: Blackwell Scientific Publications. (2nd ed.) .1962.p325 .
20. Rauch F, Plotkin H, DiMeglio L, Engelbert RH, Henderson RC, Munns C, Wenkert D, Zeitler P. Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions. J Clin Densitom.2008; 11(1):22–28.
21. Zemel BS, Leonard MB, Kelly A, Lappe JM, Gilsanz V, Oberfield S, Mahboubi S, Shepherd JA, Hangartner TN, Frederick MM, Winer KK, Kalkwarf HJ .Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab.2010; 95(3):1265-1273.
22. Sivonová M, Waczulíková I, Dobrota D, Matáková T, Hatok J, Racay P, Kliment J .Polymorphisms of glutathione-S-transferase M1, T1, P1 and the risk of prostate cancer: a case-control study. J Exp Clin Cancer Res .2009; 28:32.
23. Sharma A, Pandey A, Sharma S, Chatterjee I, Mehrotra R, Sehgal A, Sharma JK .Genetic polymorphism of glutathione S-transferase P1 (GSTP1) in Delhi population and comparison with other global populations. Meta Gene .2014; 2:134-142.
24. Adams CH, Werely CJ, Victor TC, Hoal EG, Rossouw ., vanHelden PD. Allele frequencies for glutathione S-transferase and N-acetyltransferase 2 differ in African population groups and may be associated with oesophageal cancer or tuberculosis incidence. Clin Chem Lab Med.2003; 41:600–605.
25. Dandara C, Sayi J, Masimirembwa CM.Genetic polymorphism of cytochrome P450 1A1 (Cyp1A1) and glutathione transferases (M1, T1 and P1) among Africans. Clin Chem Lab Med .2002; 40:952–957.
26. Amer MA, Ghattas MH, Abo-Elmatty DM, Abou-El-Ela SH. Evaluation of glutathione S-transferase P1 genetic variants affecting type-2 diabetes susceptibility and glycemic control . Arch Med Sci .2012; 8(4):631-636.
27. Silva DG, Belini Junior E, Torres Lde S, Ricci Júnior O, Lobo Cde C, Bonini-Domingos CR, de Almeida EA.Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia. Blood Cells Mol Dis .2011; 47(1):23-28.
28. Shiba HF, El-Ghamrawy MK, Shaheen IA, Ali RA, Mousa SM .Glutathione S-transferase gene polymorphisms (GSTM1, GSTT1, and GSTP1) in Egyptian pediatric patients with sickle cell disease. Pediatr Dev Pathol .2014; 4:265-270 .
29. Chen JT, Hosoda K, Hasumi K, Ogata E, Shiraki M .Serum N-terminal osteocalcin is a good indicator for estimating responders to hormone replacement therapy in postmenopausal women. J Bone Miner Res.1996; 11:1784-1792.
30. Eren E, Yilmaz N . Biochemical markers of bone turnover and bone mineral density in patients with beta-thalassaemia major. Int J Clin Pract .2005; 1:46-51.
31. Mlakar SJ, Prezelj J, Marc J.Testing GSTP1 genotypes and haplotypes interactions in Slovenian post-/pre-menopausal women: novel involvement of glutathione S-transferases in bone remodeling process. Maturitas .2012; 71(2):180-187.
32. Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J .Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem .1997;272(15):10004–10012.
33. Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL .Increased lipid oxidation causes oxidative stress, increased PPAR{gamma} expression and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem .2009; 284:27438–27448.
34. Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ .Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappa B. Biochem Biophys Res Commun .2004; 314(1):197-207.
35. Hoensch H, Morgenstern I, Petereit G, Siepmann M, Peters WH, Roelofs HM, Kirch W .Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system. Gut .2002; 50(2):235-240.
36. Vasieva O .The many faces of glutathione transferase pi. Curr Mol Med .2011; 11(2):129-139.
37. Yin Z, Ivanov VN, Habelhah H, Tew K, Ronai Z .Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res .2000; 60(15):4053-4057.
38. Trost Z, Trebse R, Prezelj J, Komadina R, Logar DB, Marc J . A microarray based identification of osteoporosis-related genes in primary culture of human osteoblasts . Bone .2010; 46(1):72-80.
39. Yamaguchi J, Hasegawa Y, Kawasaki M, Masui T, Kanoh T, Ishiguro N, Hamajima N .ALDH2 polymorphisms and bone mineral density in an elderly Japanese population. Osteoporos Int .2006; 17(6):908-913.
40. Miller DP, Neuberg D, de Vivo I, Wain JC, Lynch TJ, Su L, Christiani DC .Smoking and the risk of lung cancer: susceptibility with GSTP1 polymorphisms. Epidemiology .2003; 14(5):545-551.
41. Park JH, El-Sohemy A, Cornelis MC, Kim HA, Kim SY, Bae SC .Glutathione S-transferase M1, T1, and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis. Rheumatol Int .2004;24(3):157-163 .
42. Palmer CN, Young V, Ho M, Doney A, Belch JJ. Association of common variation in glutathione S-transferase genes with premature development of cardiovascular disease in patients with systemic sclerosis. Arthritis Rheum .2003;48:854–855 .
43. Hayes JD, Flanagan JU, Jowsey IR.Glutathione transferases. Annu Rev Pharmacol Toxicol .2005; 45: 51-88.
44. Ghone RA, Kumbar KM, Suryakar AN, Katkam RV, Joshi NG .Oxidative stress and disturbance in antioxidant balance in beta thalassemia major. Indian J Clin Biochem .2008; 23(4):337-340.
45. Wu KH, Chang JG, Ho YJ, Wu SF, Peng CT. Glutathione S-transferase M1 gene polymorphisms are associated with cardiac iron deposition in patients with beta-thalassemia major. Hemoglobin .2006; 30(2):251-256.
46. Origa R, Satta S, Matta G, Galanello R.Glutathione S-transferase gene polymorphism and cardiac iron overload in thalassaemia major. Br J Haematol.2008; 142(1):143-145.
47. Daar S, Pathare AV, Jain R, Zadjali SA, Pennell DJ .T2* cardiovascular magnetic resonance in the management of thalassemia patients in Oman. Haematologica .2009; 94(1):140-141.
48. Sharma V, Kumar B, Saxena R. Glutathione S-transferase gene deletions and their effect on iron status in HbE/beta thalassemia patients .Ann Hematol .2010; 89(4):411-414.
49. Zhao L, Wang Y, Wang Z, Xu Z, Zhang Q4, Yin M . Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character. J Nutr Biochem .2015;Jun 16. pii: S0955-2863(15) 00142-00144.