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Published on: May 29, 2019
GST M1 polymorphism associates with DNA oxidative damage and mortality among hemodialysis patients
Yi-Sheng Lin1, Szu-Chun Hung, Yau-Huei Wei
1Division of Nephrology, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan.
Abstract:
Leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a surrogate marker of oxidant-induced DNA damage in patients undergoing maintenance hemodialysis (MHD). Glutathione S-transferase M1 (GST M1) is a member of the GST family of proteins, which protect cellular DNA against oxidative damage. This study tested the association of a common GST M1 gene polymorphism [GST M1(-)], known to produce a dysfunctional enzyme, with levels of 8-OHdG in peripheral blood leukocytes and all-cause mortality among MHD patients. Among 488 MHD patients and 372 gender-matched healthy subjects, the frequency of the GST M1(-) genotype was 63.1 and 60.2%, respectively. The GST M1(-) genotype was associated with significantly higher levels of leukocyte 8-OHdG compared with the GST M1(+) genotype, even after adjustment for potential confounders (P < 0.001). Moreover, GST M1(-) patients who also had a common polymorphism in the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 or who underwent dialysis with a bioincompatible cellulose membrane had the highest median levels of leukocyte 8-OHdG. Multivariate Cox regression revealed that among MHD patients, GST M1(-) genotype approximately doubled the risk for all-cause mortality (hazard ratio 2.24; 95% confidence interval 1.30 to 4.51) during the mean follow-up of 34 mo. In conclusion, patients without GST M1 activity are more vulnerable to oxidative stress and are at greater risk for death compared with those who possess GST M1 activity.
Insights
Patients lacking Glutathione S-transferase M1 (GST M1) activity show increased DNA damage and a doubled mortality risk in hemodialysis. This highlights GST M1
Area of Science:
- Nephrology
- Genetics
- Biochemistry
Background:
- Leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) indicates DNA damage from oxidative stress in maintenance hemodialysis (MHD) patients.
- Glutathione S-transferase M1 (GST M1) enzymes protect DNA from oxidative damage.
Purpose of the Study:
- To investigate the association between the Glutathione S-transferase M1 (GST M1) gene polymorphism and 8-OHdG levels.
- To determine the impact of the GST M1 gene polymorphism on all-cause mortality in MHD patients.
Main Methods:
- Compared 8-OHdG levels and GST M1 genotype frequencies in 488 MHD patients and 372 healthy controls.
- Utilized multivariate Cox regression to assess mortality risk associated with the GST M1(-) genotype.
Main Results:
- The GST M1(-) genotype was linked to significantly higher leukocyte 8-OHdG levels (P < 0.001).
- Patients with GST M1(-) genotype had approximately double the risk of all-cause mortality (HR 2.24).
- Elevated 8-OHdG levels were observed in GST M1(-) patients with specific DNA repair gene polymorphisms or those dialyzed with cellulose membranes.
Conclusions:
- Individuals without GST M1 activity are more susceptible to oxidative stress and face a higher mortality risk.
- The GST M1(-) genotype is a significant risk factor for mortality in maintenance hemodialysis patients.
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