To our knowledge, this study is the first to explore the associations of GSTP1/GSTT1 genetic polymorphism with the risks of diabetes and DR in a Chinese population. In the present study, the GSTT1 null genotype was found to be an independent risk factor for the development of T2DM, whereas no significant association with DR (P = 0.65) was observed. GSTP1 also had no relationship with the development of T2DM and DR.
The GSTT1 gene is one of the most widely studied members of the GST family for its protective ability against oxidative stress in β-cells . Currently, studies regarding the role of GSTT1 polymorphism and the risk of T2DM are inconclusive because of varying reports in different studies and in people of different ethnicities. On the one hand, some studies reported that there was no association of null GSTT1 with increasing risk for the development of T2DM [29, 34, 35, 36]. For example, although the frequency of both GSTT1-null and GSTM1-null genotypes in T2DM patients was significantly higher than that in the controls, the distribution of the GSTT1 null genotype was comparable between groups in southern Iran . However, other studies reported the opposite results [14, 22, 37]. Pinheiro et al. reported that the GSTT1 polymorphism may play an important role in the pathogenesis of T2DM and complications associated with dyslipidemia in the Brazilian population . Such discrepancies may result from small sample sizes, race and methodology. Considering the controversial results in this regard, a few meta-analyses were performed, and they revealed that both GSTT1 and GSTM1 conferred increased risk for T2DM [38, 39]. Our study confirmed that the frequency of null GSTT1 was higher in T2DM patients than in controls, indicating an association of the GSTT1 null genotype and the risk of T2DM in the Chinese population. This result was consistent with the only study in Chinese people conducted by Wang et al. . The GSTT1-null allele has been reported to be associated with both macrovascular and microvascular disease in T2DM patients, including diabetic nephropathy and retinopathy [20, 26, 39, 40, 41]. In recent studies, it was demonstrated that the deletion polymorphism of GSTT1 could increase the risk for diabetic retinopathy in the Caucasian population [28, 42]. In contrast, both Dadbinpour et al. and Moasser et al. reported that there was no association between GSTT1 null genotypes and retinopathy in T2DM in the Iranian population [20, 36]. In our study, we found that the GSTT1-null genotype conferred a 1.8-fold increased risk of T2DM in subjects with and without DR compared to healthy controls (all P < 0.05). However, the frequency of the GSTT1-null genotype was comparable between T2DM patients with and without DR, indicating that there was no significant relationship between GSTT1 null genotypes and DR in T2DM in the Chinese population. Larger prospective studies are needed to confirm our findings.
Considering that GST enzyme activity was significantly lower among individuals with the 105Val allele and that genetic polymorphisms reducing the activity of antioxidant enzymes could increase a person’s susceptibility to some disease, it seems that the GSTP1 polymorphism may be associated with susceptibility to T2DM [43, 44]. However, studies regarding the association between GSTP1 polymorphism and the risk of T2DM yielded controversial results [23, 24, 25, 28, 29, 34, 42, 45, 46, 47]. Some studies suggested that the GSTP1 polymorphism was associated with susceptibility to T2DM in Caucasian and African populations [23, 24, 25, 29, 42, 46], whereas other studies did not observe a correlation between the GSTP1 polymorphism and T2DM in Caucasian and African individuals, as well as diabetes-related complications such as diabetic nephropathy in these populations [26, 34, 35, 47]. In our study, the comparison of T2DM patients with healthy controls did not reveal a significant difference in the frequency of GSTP1 genotypes, which was in accordance with previous studies. These conflicting results may be attributed to the relatively small sample size and different ethnic backgrounds of the participants. Additionally, no association was observed between the GSTP1 polymorphism and susceptibility to DR in individuals with T2DM in the present study. Thus, exploring the relationship between GSTP1 polymorphism and the risk of DR in different populations is necessary.
For the combined effect of the GSTT1 and GSTP1 genotypes and the risk of progression of T2DM and DR, a significantly higher frequency of combined GSTT1 null genotype and GSTP1 heterozygous (AG) was observed in the whole T2DM group compared with the control group (OR = 0.40, 95% CI = 0.21–0.74, P = 0.02) (Table 5). Our findings indicated that there may be an interaction or synergistic effect between each genotype, which may be more discriminating as risk factors for certain diseases.