Genetics of diabetic neuropathy: Systematic review, meta-analysis and trial sequential analysis

Objective: Diabetic neuropathy (DN) is one of the most common complications of diabetes that occurs in more than 67% of individuals with diabetes. Genetic polymorphisms may play an important role in DN development. However, until now, the association between genetic polymorphisms and DN risk has remained unknown. We performed a systematic review, meta-analysis, and trial sequential analysis (TSA) of the association between all genetic polymorphisms and DN risk. Methods: Relevant published studies examining the relationship between all genetic polymorphisms and DN were obtained based on a designed search strategy up to 28 February 2019. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess overall pooled effects of genetic models as well as in subgroup analyses. Sensitive analysis and publication bias were applied to evaluate the reliability of the study. Moreover, TSA was conducted to estimate the robustness of the results. Results: We conducted a systematic review of a total of 1256 articles, and then 106 publications reporting on 136 polymorphisms of 76 genes were extracted. We performed 107 meta-analyses on 36 studies involving 12,221 subjects to derive pooled effect estimates for eight polymorphisms. We identified that ACE I>D, MTHFR 1298A/C, GPx-1 rs1050450, and CAT -262C/T were associated with DN, while MTHFR C677T, GSTM1, GSTT1, and IL-10 -1082G/A were not. Sensitivity analysis, funnel plot, and Egger's test displayed robust results. Furthermore, the results of TSA indicated sufficient sample size in studies of ACE, GPx-1, GSTM1, and IL-10 polymorphisms. Interpretation: Our study assessed the association between ACE I>D, MTHFR C677T, MTHFR 1298A/C, GPx-1 rs1050450, CAT -262C/T, GSTM1, GSTT1, and IL-10 -1082G/A polymorphisms and DN risk. We hope that the data in our research study are used to study DN genetics.