Glutathione S-transferase genotype and risk of systemic lupus erythematosus in Koreans

Abstract

Oxidative stress caused by poor detoxification efficiency of reactive oxygen species (ROS) may play a role in the development of systemic lupus erythematosus (SLE). Glutathione S-transferase (GST) is involved in the detoxification of ROS and genetic polymorphisms of GSTM1, GSTT1 and GSTP1 are associated with altered enzyme activity. The aim of this study was to determine whether GSTM1 (deletion), GSTT1 (deletion) and GSTP1 (Ile¹⁰⁵! Val105) polymorphisms are associated with susceptibility to SLE or frequency of clinical manifestations according to the ACR diagnostic criteria. DNA was isolated from blood samples collected from 330 patients with SLE and 270 ageand sex-matched controls. GST genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No associations were observed between GSTM1, GSTT1, and GSTP1 genotypes and risk of SLE. Among SLE patients, the GSTM1 null genotype was associated with a lower frequency of hematological disorders (P = 0.012), and a higher SSA(+)/SSB(2) autoantibody profile (P = 0.042). Compared to SLE patients with the GSTT1 non-null genotype, those with the GSTT1 null genotype had a lower frequency of discoid rash (P = 0.018), and nephritis (P = 0.033). Our findings suggest that genetic polymorphisms of GSTM1, GSTT1, and GSTP1 do not influence the risk of SLE, but a deletion of either GSTM1 or GSTT1 may influence certain clinical manifestations of the disease.

Keywords

genotype glutathione oxidative stress S-transferase systemic lupus erythematosus

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References

Bae SC , Kim SJ , Sung MK. Impaired antioxidant status and decreased dietary intake of antioxidants in patients with systemic lupus erythematosus . Rheumatol Int 2002; 22: 238-243 .

Comstock GW , Burke AE , Hoffman SC et al. Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus . Ann Rheum Dis 1997; 56: 323-325 .

Suryaprabha P , Das UN , Ramesh G , Kumar KV , Kumar GS. Reactive oxygen species, lipid peroxides and essential fatty acids in patients with rheumatoid arthritis and systemic lupus erythematosus . Prostaglandins Leukot Essent Fatty Acids 1991; 43: 251-255 .

Allan IM , Vaughan AT , Milner AE , Lunec J , Bacon PA. Structural damage to lymphocyte nuclei by H2O2 or gamma irradiation is dependent on the mechanism of OH. radical production . Br J Cancer 1988; 58: 34-37 .

Evans MD , Cooke MS , Akil M , Samanta A , Lunec J. Aberrant processing of oxidative DNA damage in systemic lupus erythematosus . Biochem Biophys Res Commun 2000; 273: 894-898 .

Emlen W , Niebur J , Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus . J Immunol 1994; 152: 3685-3692 .

Blount S , Griffiths HR , Lunec J. Reactive oxygen species induce antigenic changes in DNA . FEBS Lett 1989; 245: 100-104 .

Alam K , Ali A , Ali R. The effect of hydroxyl radical on the antigenicity of native DNA . FEBS Lett 1993; 319: 66-70 .

Ahsan H , Ali A , Ali R. Oxygen free radicals and systemic autoimmunity . Clin Exp Immunol 2003; 131: 398-404 .

10.

Armstrong R. Structure, catalytic mechanism and evolution of the glutathione S-transferases . Chem Res Toxicol 1997; 10: 2-18 .

11.

Vos RM , Van Bladeren PJ. Glutathione S-transferases in relation to their role in the biotransformation of xenobiotics . Chem Biol Interact 1990; 75: 241-265 .

12.

Hayes JD , Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance . Crit Rev Biochem Mol Biol 1995; 30: 445-600 .

13.

Xu S , Wang Y , Roe B , Person WR. Characterization of the human class mu glutathione S transferase gene cluster and the GSTM1 deletion . J Biol Chem 1998; 273: 3517-3527 .

14.

Wiencke JK , Wrensch MR , Miike R , Zuo ZF , Kelsey KT. Population-based study of glutathione S-transferase mu gene deletion in adult glioma cases and controls . Carcinogenesis 1997; 18: 1431-1433 .

15.

Bruhn C , Brockmoller J , Kerb R , Roots I , Borchert HH. Concordance between enzyme activity and genotype of glutathione S-transferase theta (GSTT1) . Biochem Pharmacol 1998; 56: 1189-1193 .

16.

Zimniak P , Pikula S , Bandorowicz-Pikula J et al. Naturally occurring human GSTP1-1 isoforms with isoleucine and valine in position 104 differ in enzymatic properties . Eur J Biochem 1994; 224: 893-899 .

17.

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: 10004-10012 .

18.

Fraser PA , Ding WZ , Mohseni M et al. Glutathione S-transferase M null homozygosity and risk of systemic lupus erythematosus associated with sun exposure: a possible gene-environment interaction for autoimmunity . J Rheumatol 2003; 30: 276-282 .

19.

Ollier W , Davies E , Snowden N et al. Association of homozygosity for glutathione-S-transferase GSTM1 null alleles with the Ro+/La2 autoantibody profile in patients with systemic lupus erythematosus . Arthritis Rheum 1996; 39: 1763-1764 .

20.

Tew MB , Ahn CW , Friedman AW et al. Systemic lupus erythematosus in three ethnic groups. VIII. Lack of association of glutathione S-transferase null alleles with disease manifestations . Arthritis Rheum 2001; 44: 981-983 .

21.

Park J-H , El-Sohemy A , Cornelis MC et al. Glutatione S-transferase M1, T1 and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis . Rheumatol Int 2004; 24: 157-163 .

22.

Boumpas DT , Fessler BJ , Austin HA , 3rd et al. Systemic lupus erythematosus: emerging concepts. Part 2: Dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis . Ann Intern Med 1995; 123: 42-53 .

23.

Baud L , Ardaillou R. Reactive oxygen species: production and role in the kidney . Am J Physiol 1986; 251: F765-F776 .

24.

Adler S , Baker PJ , Johnson RJ et al. Complement membrane attack complex stimulates production of reactive oxygen metabolites by cultured rat mesangial cells . J Clin Invest 1986; 77: 762-767 .

25.

Radeke HH , Meier B , Topley N et al. Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells . Kidney Int 1990; 37: 767-775 .

26.

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 .