12 research outputs found
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
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Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes
OBJECTIVE—Despite extensive evidence for genetic susceptibility
to diabetic nephropathy, the identification of susceptibility
genes and their variants has had limited success. To search for
genes that contribute to diabetic nephropathy, a genome-wide
association scan was implemented on the Genetics of Kidneys in
Diabetes collection.
RESEARCH DESIGN AND METHODS—We genotyped
360,000 single nucleotide polymorphisms (SNPs) in 820 case
subjects (284 with proteinuria and 536 with end-stage renal
disease) and 885 control subjects with type 1 diabetes. Confirmation
of implicated SNPs was sought in 1,304 participants of the
Diabetes Control and Complications Trial (DCCT)/Epidemiology
of Diabetes Interventions and Complications (EDIC) study, a
long-term, prospective investigation of the development of diabetes-
associated complications.
RESULTS—A total of 13 SNPs located in four genomic loci were
associated with diabetic nephropathy with P1105. The
strongest association was at the FRMD3 (4.1 protein ezrin,
radixin, moesin [FERM] domain containing 3) locus (odds ratio
[OR]1.45, P5.0107). A strong association was also
identified at the CARS (cysteinyl-tRNA synthetase) locus (OR
1.36, P3.1106). Associations between both loci and time to
onset of diabetic nephropathy were supported in the DCCT/EDIC
study (hazard ratio [HR]1.33, P0.02, and HR1.32, P
0.01, respectively). We demonstrated expression of both FRMD3
and CARS in human kidney.
CONCLUSIONS—We identified genetic associations for susceptibility
to diabetic nephropathy at two novel candidate loci near
the FRMD3 and CARS genes. Their identification implicates
previously unsuspected pathways in the pathogenesis of this
important late complication of type 1 diabetes
Association of Urinary Inflammatory Markers and Renal Decline in Microalbuminuric Type 1 Diabetics
Progressive renal function decline begins in one third of patients with microalbuminuria and type 1 diabetes. This study examined whether this decline is associated with elevated excretion of inflammatory markers in urine. Five inflammatory markers (IL-6, IL-8, monocyte chemoattractant protein-1, interferon-gamma-inducible protein (IP-10), and macrophage inflammatory protein-1δ) were measured in urine samples from the First Joslin Study of the Natural History of Microalbuminuria in Type 1 Diabetes, a cohort recruited in 1991. Samples were obtained from 43 participants with microalbuminuria and stable renal function (nondecliners), from 28 with microalbuminuria and early progressive renal function decline (decliners), and from 74 with normoalbuminuria and stable renal function (reference). Urinary concentrations of all five inflammatory markers were significantly higher in decliners than in nondecliners, who were similar to the reference group. Multivariate analysis revealed that those with more than two markers elevated were more than five times as likely to have early progressive decline of renal function. In contrast, serum concentrations of C-reactive protein, IL-8, and macrophage inflammatory protein-1δ did not differ between decliners and nondecliners. These results support the hypothesis that inflammatory processes in the kidney contribute to the progression of nephropathy in patients with type 1 diabetes
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<sup>*</sup> and diabetes duration covariates.
<p>Models of association of GCH1 gene polymorphisms with outcome variables, accounting for current smoking, kidney dysfunction<sup><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108587#nt104" target="_blank">*</a></sup> and diabetes duration covariates.</p
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
Clinical characteristics of the studied T2DM patients.
<p>Clinical characteristics of the studied T2DM patients.</p
Association of individual GCH1 gene polymorphisms with outcome variables.
<p>Association of individual GCH1 gene polymorphisms with outcome variables.</p