GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus

Background: The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.<p></p> Methods: Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).<p></p> Results: Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.<p></p> Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients

Relationship between rs841 polymorphism in the 3'-UTR of GCH1 gene and vascular function measured as endothelium dependent FMD (panel A) and endothelium independent NMD) (panel B).

<p>AA indicates frequent homozygote, Aa - heterozygote, aa - rare homozygote.</p

Association of individual GCH1 gene polymorphisms with outcome variables.

<p>Association of individual GCH1 gene polymorphisms with outcome variables.</p

Relationship between studied polymorphisms and plasma vWF concentration.

<p>Relationship to polymorphisms forming haplotype block 1 (panel A) and haplotype block 2 (panel B) is demonstrated. Statistical significance of linear regression: * p<0.05.</p

Models of association of GCH1 gene polymorphisms with outcome variables, accounting for current smoking, kidney dysfunction^* and diabetes duration covariates.

<p>Models of association of GCH1 gene polymorphisms with outcome variables, accounting for current smoking, kidney dysfunction^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108587#nt104" target="_blank">*</a>} and diabetes duration covariates.</p

Clinical characteristics of the studied T2DM patients.

<p>Clinical characteristics of the studied T2DM patients.</p

Relationship between studied polymorphisms and plasma MDA concentration measured by mass-spec analysis.

<p>Relationship to polymorphisms forming haplotype block 1 (panel A) and haplotype block 2 (panel B) is demonstrated. Statistical significance of linear regression: * p<0.05; ** p<0.01.</p