Polymorphism in exon 7 of the endothelial nitric oxide synthase gene is associated with low incidence of microvascular damage in type 1 diabetic neuropathy

Abstract

Microvascular complications associated with type 1 diabetes mellitus (T1DM) are caused in part by endothelial dysfunction. We aimed to determine the association between polymorphisms in endothelial nitric oxide synthase (eNOS) gene (894G>T, 4ab) and T1DM-associated microvascular disorders, and the roles of nitrite/nitrate products (NOx) and low molecular weight-AGEs (LMW-AGEs) levels in this relationship. We carried out a case-control study (328 subjects) and determined genotypes by PCR. The rare-type TT of eNOS 894G>T was significantly overrepresented in patients without microvascular disorders as compared with control (OR=3.64; 95% C.I.=1.02–12.73; P=0.039). The prevalence of neuropathy was high among 894GG homozygotes (OR=0.5; 95% C.I.=0.29–0.86; P=0.012) who had high levels of triglycerides, elevated systolic BP, increased NOx, and LMW-AGEs. Decreased NOx levels were associated with 894TT genotype (beta=−0.65; P=0.043) in diabetic patients prone to microvascular complications. Multiple regression analysis indicated a negative correlation between eNOS 894G>T and diabetic neuropathy (P=0.025). The distribution of eNOS 4aa genotype was high (P=0.042) in patients with T1DM; however, it does not represent a risk factor for neuropathy. The overrepresentation of eNOS 894TT genotype in diabetic patients is associated with low risk for neuropathy. Decreased NOx and LMW-AGEs levels and lower lipid profile are the main features of patients carrying the eNOS 894T allele. These data suggest that the eNOS 894TT genotype may play a protective role by preventing microvascular disorders.

Genetic Determinants of Microvascular Complications in Type 1 Diabetes

“…Recent reports and our studies showed that there were no relationships between 4b/4a variant of NOS3 and DR or other microangiopathic complications. Similar results for rs1799983 in relation with DR were also reported (Heltianu et al, 2009;Mamulakis et al, 2009). In a metaanalysis of genetic association studies for DR in T1DM, from the three NOS3 polymorphisms (rs1799983, rs3138808 and rs41322052) included in the sub analysis for Caucasian subjects, none of them were found to be significantly associated with any form of DN (Abhary et al, 2009a) The progression of renal disease was associated with the NOS3 rs2070744 variant (Freedman et al, 2007;Zanchi et al, 2000), a result confirm recently by meta-analysis (Mooyaart et al, 2011;Ned et al, 2010).…”

“…It was reported that this variant changes the NOS3 protein sequence, probable resulting an alteration of enzyme activity (Costacou et al, 2006), and control the NOS3 intracellular distribution interacting with proteins of degradating process (Brouet et al, 2001). From many polymorphisms of the NOS3 gene some of them are associated with the development of diabetic microvascular complications while others indicated their protective role (Freedman et al, 2007;Heltianu et al, 2009). A recent study of rs2070744 in Caucasian T1DM reported a positive association with diabetes per se as well as DR and two possible explanations were found; either NOS3 is a candidate gene for the microvascular disease, or there is a linkage disequilibrium between NOS3 and the neighbouring genes.…”

“…Contradictory results were obtained for the relationship of NOS3 4b/4a polymorphism with DN. Some reports showed no association (Degen et al, 2001;Heltianu et al, 2009) and others indicated that the 4a allele represents an excess risk for advanced DN (Nosikov, 2004;Zanchi et al, 2000;Zinzaras et al, 2009). It was hypothesized that the NOS3 4b/4a itself plays a role in tissue-specific regulation of NOS3 expression, a mechanism related to the importance of intron structure in the splicing of immature to mature RNA or to the presence of enhancer sequences within the intron 4.…”

“…On the other hand, both rs2070744 and 4b/4a polymorphisms were specifically associated with advanced DN, and the -786C/4a haplotype was reported to be transmitted from heterozygous parents to siblings with advanced DN, suggesting that the 4a allele is coupled almost exclusively with the -786C allele of rs2070744 (Zanchi et al, 2000). The NOS3 rs1799983 was analyzed in T1DM Caucazians from different countries and some reports showed no association with DN (Heltianu et al, 2009;Möllsten et al, 2009;Nosikov, 2004) and others found a marginal relationship (Ned et al, 2010) or strong association with increased risk of DN (Zintzaras et al, 2009). The -786C/894T haplotype of NOS3 was found to be significantly associated with 13 albuminuria, suggesting a strong implication of this gene in the susceptibility to kidney damage (Ned et al, 2010).…”

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

“…[2][3][4] Nevertheless, the precise mechanisms by which hyperglycemia induce pathological outcomes and the molecular nature of its downstream effectors is still a debatable issue.…”