Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism

Abstract

Risk of advanced diabetic nephropathy in type 1 diabetes is [1][2][3][4] and may contribute to the development of diabetic associated with endothelial nitric oxide synthase gene polymornephropathy [4, 5] and premature atherosclerosis [6]. phism.This abnormality results from a decreased availability of Background. Polymorphisms in the endothelial nitric oxide nitric oxide (NO), which can be caused by impaired NO synthase gene (eNOS) may be implicated in the development synthesis or to increased NO inactivation [7, 8].of nephropathy in patients with type 1 or insulin-dependent diabetes mellitus (IDDM). Synthesis of NO is catalyzed by three NO synthases:Methods. Three groups of IDDM patients were selected to endothelial, neuronal, and inducible [9]. Encoded by sepstudy this hypothesis: cases with advanced diabetic nephropaarate genes, each isoform has a distinct pattern of expresthy (N ϭ 78), cases with overt proteinuria but normal serum sion in tissues [10]. The endothelial NO synthase gene creatinine (N ϭ 74), and controls with normoalbuminuria de-(eNOS) encoding for endothelial NO synthase is a logical spite 15 years of diabetes (N ϭ 195). Parents of 132 cases and 53 controls were also examined and were used for the target for a search for DNA sequence differences that transmission disequilibrium test, a family-based study design may contribute to endothelial dysfunction and, indito test association. rectly, to the susceptibility to the development of diabetic Results. We examined four eNOS polymorphisms, and two nephropathy [1-4].were associated with diabetic nephropathy in the case-control

A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy

“…We also found significant association in the subgroup without microalbuminuria (P = 0.018, OR = 2.14, 1.14-4.00, 95% CI). However, removing each of two studies (Zanchi et al 2000;Ahluwalia et al 2008) eliminated the association for both the allelic and recessive models of genotypic analysis (data not shown). The dominant model generated negative outcomes.…”

“…Three of these were discarded after further scrutiny: one because of patient overlap (Komatsu et al 2002), the second because the ambiguous disease status (Ohtoshi et al 2002) and the third because of unclear genotype/allele distribution (Nath et al 2009). A total of 24 references (Ahluwalia et al 2008;Ezzidi et al 2008;Kankova et al 2007;Liu et al 2005;Mollsten et al 2006;Cai et al 1998;Weekers et al 1999;Neugebauer et al 2000;Zanchi et al 2000;Fujita et al 2000;Degen et al 2001;Li et al 2001;Taniwaki et al 2001;Ukkola et al 2001;Lin et al 2002;Taverna et al 2002;Shimizu et al 2002;Ksiazek et al 2003;Rippin et al 2003;Shin Shin et al 2004;Dong et al 2007;Mollsten et al 2009;Tiwari et al 2009;Mamoulakis et al 2009) were eligible, including 30 studies. One TDT study (Zanchi et al 2000) and one perspective study (Weekers et al 1999) were excluded on the basis that they used the same samples for the case-control study in each report.…”

“…One study (Zanchi et al 2000) lacked genotype data and was, therefore, excluded from the genotypic analysis. More 894T alleles were found in Caucasian (28.7-36.6%) and Mixed (12.3-34.5%) than in East Asian (5.9-11.7%) control subjects.…”

Acidic Hydrolysis as a Mechanism for the Cleavage of the Glu298 → Asp Variant of Human Endothelial Nitric-oxide Synthase

“…To date, there are no positive studies demonstrating that mutations in the eNOS gene are causally linked to a disease process using traditional linkage analysis (7). However, in patients with coronary spasm (8) or renal disease (9), polymorphisms within the eNOS promoter have been postulated to impact levels of mRNA and protein, whereas in patients with coronary artery disease (10) or hypertension (11) polymorphisms within exon regions of eNOS may affect enzyme function. Conversely, many other studies do not show associations of the above polymorphisms with the disease (7).…”

ADPKD: molecular characterization and quest for treatment

“…Furthermore, NO inhibits platelet activation, regulates angiogenesis, and controls microvascular permeability. 100 The influence of eNOS on hypertension, coronary vasospasm, atherosclerosis and, most importantly, the progression of diabetic nephropathy, 102,103 led to the hypothesis that it could be a modifier gene in ADPKD. eNOS has a polymorphism at Glu298.…”