DR is one of the most common microvascular complications in DM patients. The hyperglycemia-induced ROS is considered as one of the initial and major pathways causing the damage to the endothelial cells. The UCPs is an anion carrier protein in mitochondrial inner membrane. UCPs function to reduce mitochondrial ROS, especially hyperglycemia-induced oxidative stress, and protect endothelial cells from oxidative stress by balancing the proton motive force across the mitochondrial inner membrane [23]. Therefore, UCPs could possibly participate in the development and pathogenesis of DR.
This meta-analysis verified the association of the reported UCPs variants with the susceptibility of DR. Our results showed that UCP1 rs1800592 variant was not significantly associated with DR in type-2 DM patients in the pooled effects analysis (Table 3 and Fig. 2); yet, in the subgroup analysis, UCP1 rs1800592 was significantly associated with PDR in type-2 DM patients in the allelic and homozygous models (Table 4 and Fig. 4). The patients carrying allele A of UCP1 rs1800592 variant have 26% higher risk developing PDR than those carrying allele G. This might be explained by a previous study demonstrated that the carriers of rs1800592 GG genotype exhibited higher UCP1 gene expression than those with AA genotype in the retina samples[17]. Conversely, UCP1 expression was lower in carriers of GG genotype than those with AA genotype in intraperitoneal adipose cells, indicated the tissue-specific effect of rs1800592 on UCP1 expression activity [36]. Moreover, allele G of UCP1 rs1800592 also showed elevated expression of MnSOD2 gene, which is another major scavenger for mitochondrial ROS [17, 37]. However, our discovery was resulted only from 2 studies. Further studies in more cohorts are needed to verify the association of this variant with PDR.
UCP2 is the most widely distributed uncoupling protein and most frequently studied in DM and DR, and itis associated with the increased oxidative stress and negatively regulates the insulin secretion [38, 39]. Total 4 UCP2 variants, UCP2 rs659366, UCP2 rs660339 (p.A55V), UCP2 45-bp Ins/Del and UCP2 rs1800849, were reported in the association analysis with DR; however, only UCP2 rs659366 variant comprised enough studies for the meta-analysis, and otherUCP2variants have not been further analyzed in this study. In this meta-analysis, we demonstrated that UCP2 rs659366 variant showed no pooled association with DR in the type-2 DM patients (Table 3 and Fig. 3). UCP2 rs659366 has been reported to be associated with type-2 DM [40]. The elevation of UCP2 expression could be induced by high glucose treatment in epithelial cell of human vein, and the A allele of UCP2 rs659366 increases promoter activity as compared to the G allele, which can be exacerbated under hyperglycemic condition to exert a protective effect [41]. The negative association of UCP2 rs659366 variant with DR in this meta-analysis might indicated that UCP2 gene variation may not be contributed to the development of DR. Nevertheless, it is of worth to note that, in the F-SNP database analyses, UCP2 rs660339 is strongly linked with UCP2 rs659366, and partially linked with UCP2 45-bp Ins/Del variant[26].One report showed that the haplotype of 3 differentUCP2 variants [Ins (45 bp Ins/Del), A (rs659366) and Ala (rs660339)] is associated with the decreased UCP2 gene expression in human retina [42].This could be an independent risk factor for PDR in both type-1 and 2 DM patients[26]. Additional association studies are necessary in order to confirm the association of all 4 UCP2 variants with DR in different ethnic groups.
We conducted the subgroup analyses on ethnicity in this meta-analysis. There was no significant association in different ethnic group, which could be due to the limited and sample sizes after stratification. Thus, the ethnicity-specific effects of these variants need to be determined with larger sample sizes in additional cohort studies.
There are several limitations in this meta-analysis. First, the number of studies for each UCPs variant was still limited. Second, the lack of original clinical information would be difficult to adjust the relevant variables, such as duration of diabetes, medications and other chronic diseases.