Epithelial nitric oxide synthases (eNOS) 894 G < T polymorphism and diabetic nephropathy susceptibility: A meta-analysis
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Hui Li
Abstract
Objective
To investigate the epithelial nitric oxide synthases (eNOS) 894 G < T polymorphism and diabetic nephropathy (DN) susceptibility by pooling the open published data.
Methods
Studies relevant to eNOS 894 G < T polymorphism and DN susceptibility published in PubMed, EMBASE, Medline, CNKI, and Wanfang databases were systematically screened by using the text words of endothelial nitric oxide synthase, eNOS, NOS-3, G894T, rs179983, polymorphism, diabetic nephropathy, and DN. The correlation between eNOS 894 G < T polymorphism and DN susceptibility was demonstrated by odds ratio (OR) and corresponding 95% confidence interval (95% CI). The data were combined through fixed or random effect model according to statistical heterogeneity. The publication bias was assessed by Begg’s funnel plot and Egger’s line regression test.
Results
Twenty-six case-control studies relevant to eNOS 894 G < T polymorphism and DN susceptibility were identified by electronic searching of the related databases. Type 2 diabetes mellitus (T2MD) patients with T allele had increased susceptibility to DN compared with G allele under homologous gene model (TT vs GG) (OR = 1.40, 95% CI: 1.16–1.69, p = 0.001), dominant gene model (TT + GT) vs GG (OR = 1.61, 95% CI: 1.30–2.00, p = 0.000) and recessive gene model TT vs (GT + GG) (OR = 1.39, 95% CI: 1.16–1.66, p = 0.000). Publication bias was not statistically significant for homologous and recessive gene model.
Conclusion
Based on the present evidence, DN risk was increased in T2MD cases with T allele compared to G allele.
1 Introduction
Diabetic nephropathy (DN), the major microvascular complication of diabetes mellitus (DM), is one of the leading causes of DM related death [1]. Epidemiology study indicated that about one-third of cases with type 2 diabetes mellitus (T2DM) would eventually develop to DN [2]. At present, the exact pathogenesis of DN is not completely clear yet. Studies have shown that persistent hyperglycemia, hypertension, and proteinuria were the major risk factors of DN [3,4]. Recently, publications also indicated that inherited factors such as single nucleotide polymorphism (SNP) of certain genes played a key role in the development of DN [5]. At present, more than ten genes have been found to be associated with DN, including inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), aldose reductase (Art), methylenetetrahydrofolate reductase (MTHFR) genes, and so on. Regulation of iNOS activity/expression and the role of iNOS agonists can be applied as potential therapeutic agents in the treatment of insulin resistance, T2DM, and heart failure [6].
Human eNOS gene is located on chromosome 7 and contains 26 exons and 25 introns with a total length of 21 kp. G894T polymorphism is the mutation of the 894 base G in the 7th exon of eNOS gene into T, which results in the change in the encoding protein product from glutamic acid to aspartic acid, and the protein structure from helix type to tight circle type, thus theoretically affecting the activity of eNOS and the production of NO and becoming an important factor of DN susceptibility. Previous studies have investigated the association of eNOS 894 G < T polymorphism and DN susceptibility, but had inconclusive conclusions. El-Din Bessa and Hamdy [7] found that the TT genotype of G894T may be the inducing factor of DN-derived end-stage renal disease in the evaluation of Egyptian population. Ezzidi et al. [8] also found that the TT genotype frequency in DM cases with DN of African population was significantly increased compared to DM patients without DN. However, Mackawy et al. [9] found no correlation between eNOS G894T and DN risk in their study of Saudi Arabian population. In order to further evaluate eNOS 894 G < T polymorphism and DN susceptibility, we searched and summarized the published literature and made the present meta-analysis.
2 Material and methods
2.1 Publication searching and inclusion
Case-control or cohort studies relevant to eNOS 894 G < T polymorphism and DN susceptibility were systematically and electronically searched in PubMed, EMBASE, Medline, CNKI, and Wanfang databases by using the text word of endothelial nitric oxide synthase, eNOS, NOS 3, G894T, rs179983, polymorphism, diabetic nephropathy, and DN. The references of the included studies were also reviewed in order to find the potential suitable publications. The studies inclusion criteria was (1) case control or cohort studies relevant to eNOS 894 G < T polymorphism and DN susceptibility; (2) studies in human being and not animal; (3) studies published in English or Chinese; (4) TT, TG, and GG allele distribution was provided or can be calculated from the original studies; (5) DN is caused by T2DM; (6) the control was T2DM cases without DN. Exclusion criteria was (1) duplicated publications or data; (2) case report of literature review; (3) not enough data especially TT, TG, and GG allele distribution was not provided in the original studies; (4) studies published in other languages and not in English or Chinese.
2.2 Data extraction
The data of each included publication were extracted by two reviewers (Hui and Guiqin) independently and made cross checking. In case of disagreement, the corresponding author (Gao) was consulted for final decision. The extracted data and information were as follows: (1) The first author’s name; (2) publication period; (3) source of literature; (4) number of patients in the original study; (5) ethnicity of patients (region); (6) Newcastle-Ottawa scale (NOS) score of each included study; (7) TT, TG, and GG allele distribution of each study; (8) Hardy–Weinberg equilibrium (HWE) of control groups.
2.3 Methodological assessment of the study
The methodological quality of each included study was evaluated by the NOS, in which a study awarded 6 or more was considered of a high-quality study, otherwise was deemed as low-quality study.
2.4 Statistical analysis
STATA16.0 statistical software was applied for data analysis. Before pooling the results, the data were examined for statistical heterogeneity by I 2 test. If statistical heterogeneity existed (I 2 > 50%, p < 0.05), the data were combined through random effect model, otherwise, by fixed effect mode. Two tails p < 0.05 was considered statistically different.
3 Results
3.1 General characteristics of the included 26 studies
After searching the relevant electronic databases and screening of studies, 26 case control studies [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] relevant to eNOS gene 894 G < T polymorphisms and risk of DN were identified and included for meta-analysis. The searched studies and inclusion flow-chart is demonstrated in Figure 1. Most of the included studies were of HWE except for Rahimi, Tiwari, and An’s work. The methodological quality of the included 26 studies was relatively high with the range of NOS score from 5 to 7. The main features of the included 26 studies are demonstrated in Table 1.
The electronic searching of publications and studies inclusion flow-chart.
The main features of the included studies
| Study | Year | Ethnicity | DN | DM without DN | HWE | NOS | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GG | GT | TT | GG | GT | TT | |||||||
| Ahluwalia et al. [24] | 2008 | South Asian | 82 | 81 | 32 | 125 | 105 | 25 | 0.669 | 6 | ||
| El-Din Bessa and Hamdy [7] | 2011 | African | 10 | 18 | 12 | 17 | 19 | 4 | 0.694 | 6 | ||
| Cai et al. [22] | 1998 | Caucasian | 65 | 44 | 7 | 148 | 109 | 27 | 0.295 | 6 | ||
| Cheema et al. [29] | 2013 | South Asian | 118 | 150 | 51 | 252 | 240 | 201 | 0.470 | 6 | ||
| Ezzidi et al. [8] | 2007 | African | 185 | 247 | 81 | 165 | 195 | 41 | 0.131 | 7 | ||
| Huo et al. [31] | 2015 | East Asian | 373 | 54 | 4 | 315 | 92 | 13 | 0.057 | 6 | ||
| Mackawy et al. [9] | 2014 | West Asian | 15 | 15 | 10 | 16 | 17 | 7 | 0.508 | 6 | ||
| Narne et al. [30] | 2014 | South Asian | 85 | 64 | 3 | 114 | 46 | 2 | 0.263 | 7 | ||
| Rahimi et al. [27] | 2012 | West Asian | 68 | 45 | 13 | 39 | 17 | 7 | 0.030 | 6 | ||
| Shoukry et al. [28] | 2012 | South Asian | 66 | 94 | 40 | 99 | 77 | 24 | 0.141 | 7 | ||
| Santos et al. [26] | 2011 | Caucasian | 176 | 166 | 32 | 118 | 95 | 22 | 0.651 | 7 | ||
| Shin Marne et al. [23] | 2004 | East Asian | 95 | 23 | 0 | 52 | 7 | 0 | 0.628 | 7 | ||
| Tiwari et al. [25] | 2009 | South Asian | 114 | 45 | 7 | 147 | 59 | 14 | 0.020 | 6 | ||
| Moguib et al. [32] | 2017 | African | 105 | 46 | 12 | 16 | 18 | 2 | 0.285 | 7 | ||
| An et al. [33] | 2015 | East Asian | 58 | 15 | 13 | 110 | 26 | 9 | <0.001 | 5 | ||
| Cheng et al. [11] | 2016 | East Asan | 23 | 18 | 0 | 22 | 12 | 0 | 0.211 | 5 | ||
| Dong et al. [12] | 2005 | East Asian | 39 | 30 | 0 | 49 | 15 | 0 | 0.288 | 7 | ||
| Dai and Zhang [13] | 2012 | East Asian | 31 | 29 | 0 | 44 | 16 | 0 | 0.233 | 6 | ||
| Fu et al. [14] | 2007 | East Asian | 33 | 28 | 0 | 64 | 14 | 0 | 0.384 | 6 | ||
| Li et al. [15] | 2002 | East Asian | 44 | 34 | 1 | 49 | 15 | 0 | 0.288 | 7 | ||
| Li et al. [16] | 2004 | East Asian | 57 | 37 | 0 | 85 | 15 | 0 | 0.417 | 7 | ||
| Lv et al. [17] | 2002 | East Asian | 44 | 34 | 1 | 49 | 15 | 0 | 0.228 | 6 | ||
| Lv et al. [18] | 2003 | East Asian | 27 | 18 | 0 | 42 | 10 | 0 | 0.443 | 7 | ||
| Ma et al. [19] | 2006 | East Asian | 125 | 42 | 0 | 115 | 17 | 0 | 0.429 | 6 | ||
| Rao et al. [20] | 2012 | East Asian | 22 | 17 | 0 | 38 | 11 | 0 | 0.376 | 7 | ||
| Wang et al. [21] | 2005 | East Asian | 33 | 28 | 0 | 64 | 14 | 0 | 0.384 | 6 | ||
4 Meta-analysis
4.1 In homologous gene model (TT vs GG)
Before data combination, the statistical heterogeneity across the included 26 studies was assessed in the aspects of homologous gene model (TT vs CC). The statistical heterogeneity was not statistically different (I 2 = 14.0%, p = 261). Thus, the odds ratio (OR) was combined through fixed effect model and results showed T2MD patients with TT allele had increased risk of susceptibility to DN compared with GG allele (OR = 1.40, 95% confidence interval (CI): 1.16–1.69, p = 0.001), Figure 2.
Forest plot of eNOS 894 G < T polymorphism and DN susceptibility in homologous gene model (TT vs GG).
4.2 In dominant gene model (TT + GT) vs GG
Due to significant statistical heterogeneity across the studies (I 2 = 75.6%, p = 0.000), the OR was combined in random effect with dominant gene model (TT + GT) vs GG. The combined data showed that susceptibility to DN in T2MD cases with TT or GT allele had significant elevated compared to cases with GG allele (OR = 1.61, 95% CI: 1.30–2.00, p = 0.000), Figure 3.
Forest plot of eNOS 894 G < T polymorphism and DN susceptibility in dominant gene model (TT + GT) vs GG.
4.3 In recessive gene model TT vs (GT + GG)
Due to non-statistical heterogeneity, the data were combined by fixed effect (I 2 = 0.0%, p = 0.462) in recessive gene model. The combined OR showed that T2MD cases with TT allele had significant elevated susceptibility to DN compared to cases with GG or GT allele (OR = 1.39, 95% CI: 1.16–1.66, p = 0.000), Figure 4.
Forest plot of eNOS 894 G < T polymorphism and DN susceptibility in recessive gene model TT vs (GT + GG).
4.4 Subgroup analysis
Subgroup analysis was made according to ethnicity. The detailed pooled ORs of different ethnicities for eNOS 894 G < T polymorphism and DN susceptibility are shown in Table 2.
ORs of different ethnicities for eNOS 894 G < T polymorphism and DN susceptibility
| Gene model | Ethnicity | No. of studies | I 2 (%) | P Q | Statistical heterogeneity | OR | 95% CI | P-value |
|---|---|---|---|---|---|---|---|---|
| Homologous (TT vs GG) | African | 3 | 31.0 | 0.235 | No | 1.86 | 1.25–2.76 | 0.002 |
| Caucasian | 2 | 0.0 | 0.353 | No | 0.83 | 0.51–1.34 | 0.435 | |
| Asian | ||||||||
| South | 5 | 42.9 | 0.136 | No | 1.58 | 1.19–2.10 | 0.002 | |
| East | 14 | 0.0 | 0.617 | No | 1.07 | 0.62–1.86 | 0.805 | |
| West | 2 | 0.0 | 0.652 | 1.23 | 0.57–2.66 | 0.591 | ||
| Dominant (TT + GT) vs GG | African | 3 | 77.0 | 0.013 | Yes | 1.04 | 0.49–2.23 | 0.914 |
| Caucasian | 2 | 4.9 | 0.305 | No | 1.02 | 0.78–1.34 | 0.874 | |
| Asian | ||||||||
| South | 5 | 52.7 | 0.0427 | Yes | 1.50 | 1.17–1.93 | 0.002 | |
| East | 14 | 82.1 | 0.000 | Yes | 2.18 | 1.40–3.40 | 0.001 | |
| West | 2 | 0.0 | 0.691 | No | 1.29 | 0.78–2.15 | 0.325 | |
| Recessive TT vs (GT + GG) | African | 3 | 0.0 | 0.412 | No | 1.77 | 1.22–2.55 | 0.003 |
| Caucasian | 2 | 0.0 | 0.454 | No | 0.80 | 0.50–1.27 | 0.339 | |
| Asian | ||||||||
| South | 5 | 3.3 | 0.388 | No | 1.61 | 1.23–2.11 | 0.001 | |
| East | 14 | 0.0 | 0.735 | No | 1.04 | 0.60–1.80 | 0.891 | |
| West | 2 | 0.0 | 0.472 | No | 1.17 | 0.57–2.42 | 0.670 |
4.5 Publication bias evaluation
In the homologous and recessive gene models, Begg’s funnel plots were general left and right symmetrical, which demonstrated no potential publication bias (Figure 5). The Egger’s line regression test also indicated non-publication bias (p homologous = 0.994, p recessive = 0.493). However, in dominant gene model, the Begg’s funnel plot was obvious left-right asymmetry (Figure 6), and Egger’s line regression test also indicated significant publication bias (p = 0.003).
Begg’s funnel plot for evaluation publication bias in homologous (a) and recessive (b) gene models.
Begg’s funnel plot for evaluation publication bias in dominant gene model.
5 Discussion
In the present meta-analysis, 26 relevant high methodological quality case-control studies were included and made data combination. Generally, the pooled data showed that T2DM patients with T allele had increased susceptibility to DN compared with G allele under homologous gene model (TT vs GG) (OR = 1.40, 95% CI: 1.16–1.69, p = 0.001), dominant gene model (TT + GT) vs GG (OR = 1.61, 95% CI: 1.30–2.00, p = 0.000), and recessive gene model TT vs (GT + GG) (OR = 1.39, 95% CI: 1.16–1.66, p = 0.000), which indicates that T2DM cases with T allele had increased risk of developing DN compared to G allele. However, subgroup analysis showed the correlation between eNOS 894 G < T polymorphism and DN susceptibility did not reach statistically significant in homologous gene model of Caucasian, East Asian, and West Asian, in dominant gene model of African, Caucasian, and West Asian, and in recessive gene model of Caucasian, East Asian, and West Asian. The non-statistically significant correlation may be due to the small sample size of the sub-group analysis.
Previous study has found that endothelial cells can produce a substance called nitric oxide (NO) that induces vascular relaxation under the induction of bradykinin [34]. NO consists of one nitrogen atom and one oxygen atom, which is a gaseous lipophilic molecule that exists for a short time. NO can regulate vascular tension, inhibit platelet aggregation and adhesion, and inhibit smooth muscle cell proliferation. As an important active substance in human body, NO also participates in various physiological and pathological regulations. Therefore, abnormal synthesis and release of NO may lead to a variety of diseases. Endogenous NO is synthesized from l-arginine guanidine terminal nitrogen atom and molecular oxygen under the catalysis of NOS. There are three NOS genes in the human genome, namely, neuronal nitric oxide synthase (nNOS or NOS-1), inducible nitric oxide synthase (iNOS or NOS-2), and endothelial nitric oxide synthase (eNOS or NOS-3). eNOS is mainly expressed in vascular endothelial cells and is involved in vascular tension. Studies have shown that eNOS plays an important role in hypertension, left ventricular hypertrophy, coronary heart disease, ischemic cerebrovascular disease, and DN [35,36].
NO can regulate renal hemodynamics and renal tubular reabsorption function, and play an important role in maintaining renal structure and function. When NO synthesis is inhibited or the concentration of NO is reduced, the renal blood flow can be reduced, and oxygen supply is affected to a certain extent, resulting in renal damage. Human eNOS gene is located on chromosome 7 and contains 26 exons and 25 introns with a total length of 21 kp. G894T polymorphism is the mutation of the 894 base G in the 7th exon of eNOS gene into T, resulting in the change in the encoding protein product from glutamic acid to aspartic acid, and the protein structure from helix type to tight circle type, thus affecting the activity of eNOS and the generation of NO and becoming an important factor of DN susceptibility. However, the meta-analysis also had limitations (1) language striction, only studies published in English or Chinese had been screened and included; (2) publication bias, signification bias existed in dominant gene model; (3) confounding factors, the pathogenesis of DN is complex and affected by multiple genes and the environment. The present meta-analysis only evaluated the susceptibility to eNOS gene G894T polymorphic site and DN risk, without considering the influence of gene–gene or gene–environment interaction; (4) small sample size for subgroup analysis, the sample size of different ethnicities was relatively small with limited statistical power.
6 Conclusion
In conclusion, our present meta-analysis demonstrated that T2DM cases with eNOS 894T allele had 1.16–1.61 times higher risk of developing DN than T2DM patients with G allele. DN risk was obviously increased in T2DM cases with eNOS 894T allele. Therefore, due to limitations of the present work, high-quality studies with large samples, multi-centers, different regions, different populations, and different types of diabetes are still needed to further clarify the relationship between eNOS gene G894T polymorphism and DN susceptibility, which is of great significance for DN screening, early diagnosis, and treatment.
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Conflict of interest: Authors state no conflict of interest.
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Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request
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© 2022 Hui Li et al., published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 International License.
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- Serum homocysteine level was elevated in ulcerative colitis and can be applied as diagnostic biomarker
- Letter to the Editor
- Serum neopterin and indoleamine 2,3-dioxyg activity are promising biomarkers for presence and progression of hepatitis B
