Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: A meta-analysis
Highlights
► It’s the first meta-analysis on this topic. ► A more precise estimate of the associations is shown in this study. ► Null genotypes of GSTM1 and GSTT1 contribute to risk of diabetes mellitus.
Introduction
Diabetes mellitus (DM), which is estimated that 347 (314–382) million adults are suffering from (Danaei et al., 2011), has become an important cause of mortality and morbidity worldwide, through both direct clinical sequelae and increased mortality from cardiovascular and kidney diseases (Danaei et al., 2006, Khaw et al., 2004, Lawes et al., 2004, Nakagami, 2004). DM results from body's ineffective use of insulin, which is determined by several different genes and environmental factors. Causes of the DM are both various and complex, and one of these causes is oxidative stress, arising as a result of an imbalance between free radicals and antioxidant defenses (West, 2000). As β-cells are very sensitive to cytotoxic stress because of their little expression of the antioxidant enzymes, they are susceptible to the oxidative stress attack, and the dysfunction of β-cells after oxidative stress attack may further result in the development of DM (Tiedge et al., 1997).
Glutathione S-Transferases (GSTs) are the most important family of phase II isoenzymes known to detoxify a variety of electrophilic compounds, including carcinogens, chemotherapeutic drugs, environmental toxins, and DNA products generated by reactive oxygen species damage to intracellular molecules, chiefly by conjugating them with glutathione (Hayes et al., 2005). GSTs play a major role in cellular antimutagen and antioxidant defense mechanisms (Baiocco et al., 2006). Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) genes are polymorphic in human and the null genotypes result in the absence of enzyme function, contributing to interindividual differences in response to xenobiotics (Binkova et al., 2007). In recent years many studies have assessed the associations between DM and GSTM1 and/or GSTT1 polymorphisms (Amer et al., 2011, Bekris et al., 2005, Bid et al., 2010, Datta et al., 2010, Hori et al., 2007, Hayek et al., 2006, Ramprasath et al., 2011, Wu et al., 2006, Wang et al., 2006, Yalin et al., 2007). Ramprasath T's study demonstrated significant associations between GSTM1/GSTT1 null genotypes and DM risk (Ramprasath et al., 2011), and similar results were also reported in other studies (Amer et al., 2011). However, some studies reported different conclusions and showed that there were no obvious associations between GSTM/GSTT1 null genotypes and DM risk (Bekris et al., 2005, Datta et al., 2010, Hori et al., 2007, Wu et al., 2006), or either GSTM1 or GSTT1 caught the associations (Bid et al., 2010, Hayek et al., 2006, Wang et al., 2006, Yalin et al., 2007). Thus, it remains unclear whether there are significant associations between GSTM1 and GSTT1 polymorphisms and DM risk.
Small genetic association studies have various designs, different methodology and insufficient power, and could inevitably increase the risk that chance could be responsible for their conclusions, while combining data from all eligible studies by meta-analysis has the advantage of reducing random error and obtaining precise estimates for some potential genetic associations. Therefore, there is a role for meta-analysis in pooling these studies, particularly to clarify the effects of GSTM1 and GSTT1 polymorphisms on DM risk. Hence, to address this controversial issue and get a more precise estimate of the associations of GSTM1/GSTT1 null genotypes with DM risk, we performed a meta-analysis of published data from available studies.
Section snippets
Search strategy and selection criteria
We collected the relative studies by conducting literature search through the PubMed, Embase and China Biology Medicine (CBM) databases (up to May 26, 2012). The search strategy included key words: (glutathione s-transferase or GST or GSTT or GSTM or GSTM1 or GSTT1) and (polymorphism or polymorphisms or genetic polymorphism) and (diabetes mellitus or DM or diabetes). The full text of the candidate articles were further examined carefully to determine whether they accorded with the inclusion
Characteristics of included studies
Following the search strategy introduced above and the selection criteria, we collected 21 records, and all of them were obtained in full-text publications. Then all the publications were further assessed for inclusion, and we excluded 10 publications, in which two for not listing available data for analysis (Oniki et al., 2008, Tiwari et al., 2009) and the others for controls containing DM patients and investigating the associations of GSTM1/GSTT1 null genotypes with DM complications (Cilensek
Discussion
GSTs are one of the major components of phase II drug-metabolizing enzymes and antioxidant systems. GSTs catalyze the conjugation of glutathione to a wide range of electrophiles and represent a protective mechanism against oxidative stress, and play a major role in cellular antimutagen and antioxidant defense mechanisms (Baiocco et al., 2006). As the strong ability to protect cell from oxidative stress damage, the GSTM1 and GSTT1 genes, which are just members of the GSTs family, have been
Conflicts of interest
None.
Author contributions
Guoliang Huang directed the whole study's design; Jingwen Zhang undertook major work of the study, including statistical operation and writing; and Hu Liu collected publications concerning the study.
Funding
None.
References (39)
- et al.
Probing the mechanism of GSH activation in Schistosoma haematobium glutathione-S-transferase by site-directed mutagenesis and X-ray crystallography
J. Mol. Biol.
(2006) - et al.
PAH-DNAadducts in environmentally exposed population in relation to metabolic and DNA repair gene polymorphisms
Mutat. Res.
(2007) - et al.
Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment
Lancet
(2006) - et al.
National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants
Lancet
(2011) - et al.
Meta-analysis in clinical trials
Control. Clin. Trials
(1986) - et al.
A common variant in the glutathione S transferase gene is associated with elevated markers of inflammation and lipid peroxidation in subjects with diabetes mellitus
Atherosclerosis
(2006) - et al.
Glutathione S-transferase A1 polymorphism as a risk factor for smoking-related type 2 diabetes among Japanese
Toxicol. Lett.
(2008) - et al.
Potential risk modifications of GSTT1, GSTM1and GSTP1 (glutathione-S-transferases) variants and their association to CAD in patients with type-2 diabetes
Biochem. Biophys. Res. Commun.
(2011) - et al.
Endothelial dysfunction: associations with exposure to ambient fine particles in diabetic individuals
Environ. Health Perspect.
(2008) - et al.
Oxidative stress pathway genes and chronic renal insufficiency in Asian Indians with Type 2 diabetes
J. Diabetes Complications
(2009)
Genetic polymorphisms of GSTT1, GSTM1, and NQO1 genes and diabetes mellitus risk in Chinese population
Biochem. Biophys. Res. Commun.
Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk
Genet. Mol. Res.
Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset
Autoimmunity
Association of glutathione S-transferase (GSTM1, T1 and P1) gene polymorphisms with type 2 diabetes mellitus in north Indian population
J. Postgrad. Med.
GSTT1 null genotype is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes, whereas GSTM1 null genotype might confer protection against retinopathy
Dis. Markers
The combination of estimates from different experiments
Biometrics
Association of glutathione S -transferase M1 and T1 gene polymorphism with oxidative stress in diabetic and nondiabetic chronic kidney disease
Ren. Fail.
Increased cardiovascular morbidity and mortality in Type 2 diabetes is associated with the glutathione S transferase theta-null genotype:a Go-DARTS study
Circulation
Bias in meta-analysis detected by a simple, graphical test
BMJ
Cited by (34)
The combined effects of GSTM1/GSTT1 and MTHFR C677T polymorphisms on the systemic arterial hypertension susceptibility: A genetic association study in Brazilian diabetic patients
2023, Human GeneCitation Excerpt :It appears that the GSTT1 null genotype confers risk possibly affecting the functional effect of the GSTM1 present genotype. In addition, the oxidative effects of the genotypic combinations GSTT1 null/GSTM1null and GSTT1null/GSTM1 present have also been reported in the development of schizophrenia (Pinheiro et al., 2017), DM (Pinheiro et al., 2013; Zhang et al., 2013), CVDs (Almoshabek et al., 2016), DN (De Lima et al., 2018), and SAH (Rizvi et al., 2015). Moreover, it's known that the GST double null genotypes impair the cellular detoxification process with consequent accumulation of ROS and endothelial injury (Cuevas and Villar, 2019; Meza et al., 2019; Rong et al., 2019).
Deep learning approach identified a gene signature predictive of the severity of renal damage caused by chronic cadmium accumulation
2022, Journal of Hazardous MaterialsCitation Excerpt :Interestingly, GSTM1 is highly polymorphic. Various single nucleotide polymorphisms (SNPs) of GSTM1 have been reported to be associated with human diabetes (Nath et al., 2019; Zhang et al., 2013) and the plasma cadmium level as well as susceptibility to cadmium-induced toxicity (Aliomrani et al., 2017; Khansakorn et al., 2012; Yohannes et al., 2021). Moreover, various studies also indicated that GSTM1 plays an important role in kidney diseases.
No association between GSTM1 and GSTT1 deletion polymorphisms and Amyotrophic Lateral Sclerosis: a genetic study in Brazilian patients
2021, Meta GeneCitation Excerpt :This fact may explain the non-significant association between these polymorphisms and the ALS susceptibility (Fuciarelli et al., 2009; Eslami and Sahebkar, 2014; Mazzetti et al., 2015). Studies point to the relationship between GSTM1 and GSTT1 deletion polymorphisms in the pathogenesis of diseases, such as schizophrenia (Pinheiro et al., 2017), diabetes mellitus (Pinheiro et al., 2013; Zhang et al., 2013), and diabetic nephropathy (De Lima et al., 2018). However, no studies have evaluated the association between GSTM1 and GSTT1 genes in the pathogenesis of ALS, especially in Brazilian population.
Effect of the GSTM1 gene deletion on glycemic variability, sympatho-vagal balance and arterial stiffness in patients with metabolic syndrome, but without diabetes
2018, Diabetes Research and Clinical PracticeCitation Excerpt :However, numerous studies investigated the role of GSTM1 deletion polymorphisms in the pathogenesis of diabetes mellitus. Even in this case, the results are often controverting due to heterogeneity in ethnicity and genetic background [38], but in general the deletion of GSTM1 seems to be a genetic risk factor in the diabetes development [39]. An association between GSTM1 deletion polymorphism and changes in the glycemic parameters in diabetic patients has also been investigated.