NADPH oxidase p22phox C242T polymorphism is associated with macroalbuminuria in diabetic patients: A meta-analysis

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Abstract

Aims

Previous studies suggested an association between C242T polymorphism in NADPH Oxidase p22phox and diabetic nephropathy (DN) risk, but the results were inconsistent. To obtain a more precise estimation, we carried out a meta-analysis to analyze the effect of C242T polymorphism in NADPH Oxidase p22phox on DN risk.

Methods

We searched PubMed, ISI Web of Science, and China National Knowledge Infrastructure for all eligible case–control studies through May 2016. The odds ratios (ORs), together with the 95% confidence intervals (CIs), were calculated to evaluate the strength of association between C242T SNP in NADPH Oxidase p22phox on DN risk.

Results

Overall, ten eligible studies involving a total of 1894 cases and 1746 controls were included in our meta-analysis. The results showed that there was no statistical evidence of association between NADPH oxidase p22phox C242T polymorphism and DN in all genetic models (T vs. C: OR 1.16, 95% CI 0.85–1.59, p = 0.34; TT vs. CC: OR 1.49, 95% CI 0.80–2.76, p = 0.21; TT/CT vs. CC: OR 1.18, 95% CI 0.81–1.72, p = 0.40; TT vs. CT/CC: OR 1.31, 95% CI 0.82–2.11, p = 0.26). However, significant association was found in diabetic patients with macroalbuminuria.

Conclusion

This meta-analysis indicates that NADPH oxidase p22phox C242T polymorphism is associated with macroalbuminuria in diabetic patients. However, this conclusion should be interpreted with caution due to the small sample size. Larger sample-size studies with homogeneous patients and well-matched controls are required.

Introduction

Diabetic nephropathy (DN) is a major complication of diabetes mellitus and is the leading cause of end-stage renal disease (ESRD). ESRD has become a threat to the health and heavy burden for families and society. Renal pathophysiology involves multiple interconnected pathways including polyols, hexosamines, oxidative stress, PKC activation and advanced glycation end products (AGE) formation or inflammation.1 Reactive oxygen species (ROS) produced continuously by the cellular metabolism and playing multiple roles in the physiological control of cell functions,2 plays a pivotal role in the pathophysiology of diabetic nephropathy, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system is an important source of ROS in hyperglycemic conditions in the kidney. The NADPH oxidase system such as p22phox, p40phox, p47phox, p67phox, Rac-1, and Nox2,3, 4 are expressed in several tissues and cells to produce reactive oxygen species (ROS) involved in the control of the redox balance and oxygen sensing.5 The CYBA gene encoding p22phox is located on chromosome 16q24 with several genetic variants and is essential for the activation of NADPH oxidase.6, 7, 8 Several polymorphisms of the CYBA gene have been reported, which could lead to significant functional variation among individuals in oxidative stress by influencing gene expression and NADPH oxidase activation.9, 10, 11 Among them, the C242T (His72Tyr; rs4673), a well-studied one, leads to the change of His72Arg in p22phox, which is surmised to contribute to an inter-individual variation in vascular superoxide (O2) generation. Because the histidine residue is a candidate for the coordinating ligand of the heme prosthetic group of cytochrome b, this polymorphism has been suggested to be directly associated with the function of p22phox. The association between C242T polymorphism with diabetic nephropathy risk has been a research focus and has drawn increasing attention. Therefore, we performed the present meta-analysis synthesizing the data from the previous published studies to evaluate the genetic risk of NADPH Oxidase p22phox C242T polymorphism for diabetic nephropathy.

Section snippets

Literature search

We conducted an electronic search for the relevant articles published in the following databases: PubMed, ISI Web of Science, and China National Knowledge Infrastructure from the established date to May 2016, using the search terms or their combinations as follows: “NADPH oxidase”; “p22phox”; “CYBA”; “C242T”; “diabetic nephropathy”. The reference lists were also scanned to acquire the additional unfound relevant articles.

Selection criteria

All of the included original studies were selected according to the

Literature search and study characteristics

A total of 95 articles were identified through the initial search in the database. Based on the selected criteria, we screened the titles and abstracts of the initial publications and obtained 12 potential articles.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 After scanning the full texts, three articles were excluded. Among them, one article did not provide sufficient information of p22phox gene C242T polymorphism.12 One study that deviated from HWE (16;) and one study that focused on

Discussion

The genetic susceptibility to diabetic nephropathy has been the focus of research in the scientific community. This meta-analysis summarized all of the available data on the effect of C242T polymorphism in NADPH Oxidase p22phox on DN risk. In overt DN, a significant association was found for the genetic models examined. In addition, heterogeneity decreased when this population was viewed as a separate group, which suggested that the effect of the T allele on the risk of DN might differ.

Reactive

Acknowledgement

This work was supported by grants from the National Natural Science Foundation of China (No.81370919, No.31571186).

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  • Conflict of interest: None.

    1

    R.N. Tang, P. Wu, and L. An contributed equally to this work and should be considered as co-first authors.

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