It has become one of the main foci of fundamental researches in DR to unravel those genes that accelerate the pathogenic risk of DR among the diabetic patients over the past few decades. A growing number of putative genes and genetic variants have been discussed to investigate the genetic risk loci having a relationship with DR . Functional studies have indicated a vital role for TNF as a biomarker in DR. Experimental studies in animal diabetic models have suggested that TNF-a is responsible for capillary degeneration, pericyte loss and so on, which all are features of DR. Nevertheless, the association between TNF-a polymorphism and the occurrence and progression of DR still remained conflicting as a result of controversial findings generated by some relatively small researches. The first meta-analysis conducted by Meng et al., showed that there was no obviously statistical difference between T2DM with or without retinopathy and TNF-308 G>A polymorphism.
Available data concerning the association between TNF-308 G>A polymorphism and DR risk in 8 studies, which involve 1,698 DR cases and 2,064 controls, were calculated in the present meta-analysis. Insignificant heterogeneity was detected among all those five models. Under the codominant model (GA versus GG), the dominant model [(GA + AA) versus GG] and the allelic model (A allele versus G allele), all summary ORs indicated that TNF-308 G>A polymorphism was marginally significantly related with an increased risk of DR. As ethnic differences may lead to different genetic backgrounds, and then may have an influence on genetic predispositions in some pathological conditions [29,30], the subgroup analysis was also further performed divided by ethnicity. In the stratified analysis, significantly statistical differences were observed with European ethnicity. Furthermore, there is evidence showing that genetic predisposition is more probable in type 1 DM in some genes. For example, Zhou et al., have proved that a genetic relationship between aldose reductase C(-106)T polymorphism and DR risk of T1DM but not T2DM. As a result, we further explored the difference in the separate analysis of T1DM and T2DM. However, the results implied a lack of association between TNF-a -308 G>A polymorphism and the type of DM. What’s more, it is worth noting that the controls’ genetic distributions in the research conducted by Bućan et al.in 2009 deviated from HWE, supporting the probability of bias. Therefore, we undertook the sensitivity analysis afterwards to omit it. And the findings from the overall ORs before and after omitting the research were consistent, indicating that there was little effect to the result of this meta-analysis by the study. Furthermore, no significant publication bias was found in the pooled results in any genetic model, which further demonstrated the robustness of our meta-analysis.
The earliest investigation into TNF-a polymorphism and DR risk, reported by Wang et al., revealed a negative relationship between the -308 A allele of TNF-a and DR risk in Chinese patients. However, owing to the essential information is not enough, we excluded this study in our meta-analysis. In the subsequent studies, it was suggested that there was a trend of lacking association [20,19,17,16,15,14]. But in a larger case-control study in Scandinavia that contained a total of 622 patients with T1DM and 878 patients with T2DM, Lindholm et al. reported a significantly higher frequency of A allele (OR: 1.53, 95%CI 1.04 to 2.25) in T2DM with DR but not in T1DM, indicating -308 A allele in TNF-a locus as a risky factor for DR. And the research manifested by Sesti et al. is in consistent with the research above. Our meta-analysis confirmed that the -308 A allele of the TNF-a carried more risk in European but not Asian participants, even if the overall effect was positive. What’s more, all the studies in Asian populations showed no relationship between TNF-a polymorphism and DR risk. The divergences in ethnic backgrounds, living environment, nutrition and lifestyle may partly account for the discrepancy.
Further, several studies had also focused on the question that whether there is a certain connection between TNF-a polymorphism and different stages of DR, such as NPDR and PDR[23,22,24]. However, there was no significant association to be found between the promoter polymorphism and different DR phenotypes.
There are several major differences between the previous meta-analysis, performed by Meng et al. and our study. First, the authors made a conclusion that there was no association between TNF-a -308 G>A (rs1800629) polymorphism and DR in T2DM, while we found TNF-a polymorphism may be associated with increased DR risk among DM patients, especially among the European population. Second, they did not included the study deviating from HWE, and this may result in the loss of some data and thus lead to the incomprehensiveness of the meta-analysis. We included the study conducted by Bućan et al. in 2009. At the same time, a sensitivity analysis was performed to detect whether the study affected the pooled result. Third, the sample being made use of in this research was larger than that in the previous meta-analysis. We included 3 case-control studies which are published later, and thereby it could strengthen the statistical efficiency and elevate the credibility of the outcomes.
A few of potential limitations existed in our study and the results should be interpreted carefully. First, our meta-analysis is based on unadjusted estimates due to a lack of original data. For example, the accurate disease’s time-course of each patients was not available. Therefore, our classification criterion could not be performed according to the duration of the diabetes, which may affected the results. Second, it should be noticed that there was one study deviating from HWE. This possibly have enhanced the possibility of selective bias in controls. However, when the research was eliminated, the pooled OR of the rest studies was invariant, which indicated the fairly good stability of the findings in our meta-analysis. Third, the sample size of this meta-analysis was limited, although the Egger’s test indicated no publication bias. Fourth, genotyping methods were various among those included studies, which might influence the outcomes. This discrepancy suggests the necessity to carry out strict quality control procedures in future researches.