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Author's response to reviews Title : Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy : a systematic review and meta-analysis
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dellaméa, Bruno Schmidt Pinto, Lana C. Leitao, Cristiane Bauermann Santos, Kátia G. Canani, Luís Henrique |
| Copyright Year | 2013 |
| Abstract | Background: Endothelial nitric oxide synthase gene (eNOS-3) polymorphisms have bee n associated with diabetic nephropathy (DN), however some studies do not co firm this association. Therefore, we conducted a systematic review and meta-analysis, including studies with diabetic patients with nephropathy (cases) and diabetic patient s without nephropathy (controls) that evaluated at least one of the three polymorphisms of interest. All studies published up to December 31 , 2012 were identified through electronic databases. Gene-disease associati on was measured using odds ratio estimation based on the following gene tic contrast/models: (1) allele contrast; (2) additive; (3) recessive; (4) dominant, and (4) codominant. The analyzed polymorphisms in eNOS-3 gene were 4b/4a, T-786C, and G986T. Results: Twenty-two studies were eligible for meta-analysis (4b/a: 15 studies, T-786C: 5 studi es, and G984T: 12 studies). Considering 4b/a polymorphism, an association with DN was observed for a ll genetic models: allele contrast (OR=1.14, CI:1.04-1.25); additive (OR=1.77, CI:1.37-2.28); reces sive (OR=1.77, CI:1.38-2,27); dominant (OR=1.12, CI:1.01-1.24), with the exception for co-dominance model . As well, T-786C polymorphism showed association with all models, with e xception for codominance model: allele contrast (OR= 1.22, CI: 1.07-1.39), additive (OR = 1.52, CI: 1.18-1.97), recessive (OR = 1.50, CI: 1.16-1.93), and dominant (OR = 1.11, CI: 1.01-1.23). For the G 894T polymorphism, an association with DN was observed in allelic contrast (OR = 1.12, CI: 1.031.25) and co-dominance models (OR= 1.13, CI: 1.04-1.37). Discussion: In the present study, there was association of DN with eNOS 4b/a and T-786C polymorphism, whi ch held in all genetic models tested, except for co-dominance model. G894T polymorphism wa associated with DN only in allele contrast and in co-dominance model. This data suggested that the eNOS gene could play a role in the development of DN. Introduction Nitric oxide (NO) is a short-lived gaseous lipophilic molecule produce in almost all tissues and organs[1-2]. It is a free radical that exerts a var iety of biological actions under both physiological and pathological conditions[3]. NO is formed from its pr ecu sor L-arginine by a family of NO synthases (NOSs). NOS system consists of three distinct isoforms, encoded by three distinct genes, including neuronal (nNOS or NOS-1), inducible ( iNOS or NOS-2), and endothelial (eNOS or NOS-3). The gene encoding eNOS is located on chromosome 7 (7q35-q36) and contains 26 exons, with an entire length of 21 kb[3-4] NO has numerous functions in the kidney, including control of renal and glome rular hemodynamics, by interfering at multiple pathological and physi olog cally critical steps of nephron function. NO dilates both the afferent and the efferent arteri ole, augmenting the glomerular filtration rate (GFR) and influencing renal sodium handli ng [5]. NO also mediates pressure natriuresis, maintenance of medullary perfusion, decrease of tubuloglomerular reabsorption, and modulation of renal sympathetic nerve activity [6]. The net ffect of NO in the kidney is to promote natriuresis and diuresis, along with renal adapta tion o dietary salt intake [78]. eNOS gene has been considered a potential candidate gene to diabet ic nephropathy (DN) susceptibility. Since 1998 , several polymorphisms of the eNOS gene have been identified, and their association with various diseases has been explored. T hree polymorphisms have been the subject of research in relation to DN, however the results are highly variable. The polymorphisms potentially associated with DN are a 27-bp repeat in i n ron 4 (VNTR), the T786C single nucleotide polymorphism (SNP) in the promoter region (rs2070744), and G894T missense mutation in exon 7 (rs1799983) [9]. Some of these polymorphisms are a sociated with reduction of either eNOS activity (-786C in the promoter area) or pl asma concentrations of NO (four repeats in intron 4) [2]. However, the potential association of eNOS gene variants with the induction and progression of DN remains controversial. Some authors found a higher fre quency of eNOS polymorphisms in patients with end-stage renal disease (ESRD) and D N [10-17], but not all studies reported this association [18-20]. The objective of the present study was to evaluate if eNOS ge ne polymorphisms are associated with DN through a systematic review of the literature and a met a-analysis. Results and discussion Three-hundred and nine studies were identified, and 281 were excluded based on review of titles and abstracts (70 animal experimental studies, 17 pharmac ological studies, 86 without adequate cases or controls, 58 without the genes or polymorphisms of inter est, 3 review articles, 5 meta-analysis, 35 studies with multiple publications of the same data presented with different titles, 7 no accesses to original data even after contacting author s). Twenty-eight articles were eligible and had the full text evaluated. Six studies were exc luded due to lack of information regarding genotypic distribution. A total of 22 studies fulfilled the eligible criteria and were included for the meta-analysis (Figure 1). Clinical characteristics of individual studies are described in Table 1. Regarding quality assessment, the phenotype definitions as cases or controls were appr opri ted, but none of the studies included information if genotyping was performed by personnel bl i ded to clinical status. Of the 22 studies included, 15 provided 4054/3405 cases/controls for 4b/a; 5 provided 1436/1286 cases/controls for T-786C; and 12 provided 3316/2765 cases/controls for G894T. The allelic frequency of 4b, T-786, and G894 in cases/controls was 6647/5702, 1863/1795, and 4691/4017 respectively (Table 2). Hardy-Weinberg equilibrium (HWE) was assessed using exact te st and P-value < 0.05 were considered significant. Only 4 studies (1 study for T-786C; 2 for G984T; and 1 for 4b/a) with controls were not in HWE (Table 2). These studies were subje cted to a sensitive analysis, and their exclusion did not show significant difference on OR. For the 4b/a polymorphism, an association with DN in all genetic models , except for codominance, was observed: allele contrast (OR= 1.15, CI(95%): 1.05-1.25, P Q <0.01, I 2 = 66%); additive (OR= 1.52, CI(95%): 1.18-1.97, P Q <0.01, I 2 = 62%); recessive (OR= 1.50, CI(95%): 1.16-1.93, PQ <0.01, I 2 = 64%); and dominant (OR= 1.11, CI(95%): 1.01-1.23, P Q= 0.01, I 2 = 49%). Similarly, for the T-786C polymorphism the association with D N was found with all models, with exception for co-dominance model: allele contrast (OR = 1.22, CI (95%): 1.07-1.39, PQ= 0.59, I 2 = 0%), additive (OR = 1.52, CI (95%): 1.18-1.97, P Q<0.01, I 2 = 62%), recessive (OR = 1.50, CI (95%): 1.16-1.93, P Q <0.01, I 2 = 64%) and dominant (OR = 1.11, CI (95%): 1.01-1.23, PQ <0.01, I 2 = 49%). The G894T polymorphism showed association with DN in allelic contrast (OR = 1.12, CI (95%): 1.03-1.25, P Q <0.01, I 2 = 75%) and co-dominance model (OR= 1.13, CI (95%): 1.04-1.37, P Q= 0.01, I 2 = 60%). (Table 3 and Figure 2). A random model analysis was performed confirming the fixed model results. Publication bias was observed for the majority of the polymorphisms e valuated and are presented as a funnel plot for 4b/a polymorphsism. (Figure 3). In order t identify non published data, we performed manual search for abstracts in some of the ma jor scientific meetings in the field in the last seven years. We estimated the effect of t hese potential publication biases using trim and fill method and no major differences were observed from the original result s. Since some studies included only subjects of specific ethnicities or with type 1 or type 2 DM, we performed a sensitive analysis stratifying the studies according to these characteristics. Considering 4b/a polymorphism, there was an association in White and Eas t Asi n populations in allele contrast, additive and recessive models; only for Whites in the dominant model; and none for the co-dominant model. For T-786C variant, no association was shown f or Whites in allele contrast analysis or in any other genetic model, but in Af rican populations the polymorphism was associated with DN in allele contrast, dominance a nd co-dominance models. Considering G894T polymorphism, in African populations the association was observed for all genetic models, with the exception of co-dominance model. There wer e insufficient studies to perform a meta-analysis for G894T in South Asians and West Asians. According to the type of diabetes mellitus (DM), for 4b/a polymorphi sm an association was observed in additive and recessive models for both type 1 and type 2 diabetes, and only for type 1 in allele contrast and dominant models. There was no associa tion with any type of DM in co-dominant model for 4b/a variant. For T-786C, no association in any genet ic model was found in type 2 diabetes. There was insufficient data for this analys is in type 1 DM. Likewise, for G894T variant there was an association only in the allele contrast model with type 2 diabetes |
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