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

Wolkow PP, Kosiniak-Kamysz W, Osmenda G, Wilk G, Bujak-Gizycka B, Ignacak A, Kanitkar M, Walus-Miarka M, Harrison DG, Korbut R, Malecki MT, Guzik TJ - PLoS ONE (2014)

Bottom Line: 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).Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.

View Article: PubMed Central - PubMed

Affiliation: Centre for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland; Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland.

ABSTRACT

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.

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).

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.

Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.

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Related in: MedlinePlus

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).AA indicates frequent homozygote, Aa - heterozygote, aa - rare homozygote.
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pone-0108587-g002: 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).AA indicates frequent homozygote, Aa - heterozygote, aa - rare homozygote.

Mentions: We next studied the associations between each of the 5 genotyped SNPs, as well as each of the 2 haplotype blocks formed by these SNPs, with outcome variables (Table 2). Polymorphism rs841 was associated with endothelial function measured as maximal FMD (Figure 2A), while no association was found with control NMD (Figure 2B). Three polymorphisms belonging to the same haplotype block (rs10483639, rs841, and rs3783641) were associated with vWF concentration, a plasma biomarker of endothelial function - (Figure 3A and B). In the case of the last polymorphism, rs3783641, for the genotype mean value of vWF concentration we observed no progression from Aa to aa genotypes. This may suggest either a non-additive model of association or simply reflect the fact that there were only 6 people with the aa genotype in our study. Interestingly, 4 polymorphisms (rs10483639, rs841, rs3783641, and rs8007267) were also associated with plasma MDA concentration, a systemic oxidative stress marker (Figure 4A and B).


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

Wolkow PP, Kosiniak-Kamysz W, Osmenda G, Wilk G, Bujak-Gizycka B, Ignacak A, Kanitkar M, Walus-Miarka M, Harrison DG, Korbut R, Malecki MT, Guzik TJ - PLoS ONE (2014)

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).AA indicates frequent homozygote, Aa - heterozygote, aa - rare homozygote.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219671&req=5

pone-0108587-g002: 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).AA indicates frequent homozygote, Aa - heterozygote, aa - rare homozygote.
Mentions: We next studied the associations between each of the 5 genotyped SNPs, as well as each of the 2 haplotype blocks formed by these SNPs, with outcome variables (Table 2). Polymorphism rs841 was associated with endothelial function measured as maximal FMD (Figure 2A), while no association was found with control NMD (Figure 2B). Three polymorphisms belonging to the same haplotype block (rs10483639, rs841, and rs3783641) were associated with vWF concentration, a plasma biomarker of endothelial function - (Figure 3A and B). In the case of the last polymorphism, rs3783641, for the genotype mean value of vWF concentration we observed no progression from Aa to aa genotypes. This may suggest either a non-additive model of association or simply reflect the fact that there were only 6 people with the aa genotype in our study. Interestingly, 4 polymorphisms (rs10483639, rs841, rs3783641, and rs8007267) were also associated with plasma MDA concentration, a systemic oxidative stress marker (Figure 4A and B).

Bottom Line: 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).Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.

View Article: PubMed Central - PubMed

Affiliation: Centre for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland; Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland.

ABSTRACT

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.

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).

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.

Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.

Show MeSH
Related in: MedlinePlus