Candidate-gene association studies that examined the association between polymorphisms of endothelial nitric oxide synthase (NOS3) gene (G894T, 4b/a, and T786C) and diabetic nephropathy or diabetes leading to severe nephropathy produced inconclusive results. Thus, a meta-analysis of all candidate-gene association studies with endothelial nitric oxide synthase genotyping (7401 cases and 8046 controls) was conducted. Other study designs, such as family-based association studies and genome-wide linkage and association studies were also reviewed for supportive evidence of implication of endothelial nitric oxide synthase gene in diabetic nephropathy. The meta-analysis showed that G894T is significantly associated with diabetic nephropathy and diabetes leading to severe nephropathy in type 2 diabetics and in East Asians, respectively. Concerning the 4b/a polymorphism and its relationship to diabetes leading to severe nephropathy, a significant association was shown for East Asians. Heterogeneity between studies was in general high. There was no differential magnitude of effect in large versus small studies. One genome-wide linkage scan provided evidence of linkage nearby the endothelial nitric oxide synthase locus. Studies exploring gene and environment interactions with endothelial nitric oxide synthase polymorphisms may help understand better the genetics of diabetic nephropathy. Genet Key Words: eNOS, NOS3, G894T, 4b/a, T786C, diabetic nephropathy, diabetes, polymorphism, meta-analysis, genetic epidemiology Gene and gene variantsVascular endothelial nitric oxide (NO) regulates endothelial function and precipitates vasodilatory effects in multiple organs, including the kidney. 1 NO is produced by the oxidation of L-arginine to L-citrulline by NO synthase (NOS). There are three isoforms of NOS: endothelial NOS (eNOS), neuronal NOS, and inducible NOS. 2,3 Each isoform is coded by separate genes with a different pattern of expression. 4 The eNOS gene (NOS3) is located on chromosome 7q35-36, and it comprises 26 exons and 25 introns, with an entire length of 21kb. 4 Variants of eNOS gene contribute to endothelial dysfunction and attenuate the NO production. 5 Dysfunctional eNOS may play a critical role in the pathogenetic pathway, leading to diabetic vascular complications including diabetic nephropathy (DN). 6 Several polymorphisms of the eNOS gene have been identified, and their association with various diseases has been investigated, including coronary artery disease, myocardial infarction, coronary spasm, hypertension, end-stage renal disease (ESRD), and DN. 4,[7][8][9][10] The most clinically relevant polymorphisms that have been described in the eNOS gene 11 are the following: (i) a G894T substitution in exon 7 that results in a Glu to Asp substitution at codon 298, 7 (ii) an insertion-deletion in intron 4 consisting of two alleles (the a-deletion has 4 tandem 27-bp repeats, and the b-insertion has 5 repeats), 12 and (iii) a T786C substitution in the promoter region, which is strongly linked to 4b/a....

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Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case-control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and casecontrol studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (P Q \ 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03-1.64). However, the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10-1.58), P Q = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06-1.60), P Q = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13-2.42), P Q \ 0.01] in Caucasians [FE OR = 1.48 (1.11-1.98), P Q = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03-2.67), P Q \ 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.

Altered expression of the facilitated glucose transporter GLUT1 affects pathways implicated in the pathogenesis of diabetic nephropathy. There is indication that variation of GLUT1 gene (SLC2A1) contributes to development of microangiopathy in diabetes mellitus type 2 (DM) patients. A genetic association study involving Caucasians was carried out to investigate the role of XbαI polymorphism in the GLUT1 gene in diabetic nephropathy (DN). Study population (n = 240) consisted of 148 unrelated patients with DM (92 cases with diabetic nephropathy (DN)), and of 92 matched healthy control subjects. Diabetic nephropathy was defined as persistent albuminuria (> 300 mg/24 h) and/or renal failure, in the absence of non-diabetes induced renal disease. The analysis showed that the risk of developing DM and DN in XbaI(−) carriers, when healthy individuals were considered as controls, was two-fold: odds ratio (OR) 2.08 [95% confidence interval (1.14–3.79)]. However, there was no evidence of association between XbaI(−) and DN when patients with DM and without DN were considered as controls: OR = 1.12 (0.55–2.26). Thus, the GLUT1 XbaI(−) allele is associated with DM, and possibly with a more severe form of the disease that can lead to development of DN.