| 1. |
- Möllsten, Anna, et al.
(författare)
-
The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes
- 2009
-
Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192 .- 1096-7206. ; 97:1, s. 80-84
-
Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) is important in the maintenance of vascular tone and regulation of blood pressure. NO may also play a role in the development of both nephropathy and cardiovascular disease (CVD) in patients with diabetes. The susceptibility to nephropathy and CVD depends to some extent on genetic factors, therefore polymorphisms in the gene coding for endothelial NO-synthase, NOS3, can affect the risk of developing these diseases. Type 1 diabetes patients attending the Steno Diabetes Center, Denmark, between 1993 and 2001 were enrolled in this study. A total of 458 cases with diabetic nephropathy (albumin excretion >300 mg/24h) and 319 controls with persistent normoalbuminuria (<30 mg/24h), despite > or =20 years of diabetes duration at follow-up were identified. Patients were followed until death or end of the study. Associations between seven NOS3-gene polymorphisms and nephropathy, progression of nephropathy and CVD were studied. There was significant association between the rs743507 TT-genotype and diabetic nephropathy. When including age at diabetes onset, diabetes duration at follow-up, baseline Hb(A1c), sex and ever smoking in the analysis the OR was 1.43 (95% CI=1.03-2.00), P=0.035. In analyses of CVD development using Cox-regression the rs1799983 GG-genotype was a significant protective factor in normoalbuminuric patients, HR=0.32 (0.12-0.82), P=0.018, but not in patients with macroalbuminuria (covariates were; age at follow-up, baseline Hb(A1c), baseline systolic blood pressure, baseline cholesterol, sex and ever smoking). Our conclusion is that the NOS3-gene may be involved in the development of diabetic nephropathy in patients with type 1 diabetes and can be predictive of CVD during follow-up.
|
|
| 2. |
- Palm, Fredrik
(författare)
-
Commentary on Wilcken et al. Asymmetric Dimethylarginine (ADMA) in Vascular and Renal Disease
- 2007
-
Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192 .- 1096-7206. ; 91:4, s. 308-
-
Tidskriftsartikel (refereegranskat)abstract
- Wilcken and co-workers summarize our current knowledge about the role of asymmetric dimethylarginine (ADMA) as a key regulation of nitric oxide (NO) production, and examine the putative role of ADMA in the development of vascular and organ dysfunction [1]. Impaired NO production is closely associated with vascular dysfunction, especially during states of increased oxidative stress such as smoking, renal dysfunction requiring dialysis, hypertension and diabetes. Vallance et al. early identified increased ADMA levels in patients requiring dialysis, a state commonly associated with vascular dysfunction [2]. ADMA competitively inhibits NOS and competes with arginine for cellular uptake via the cationic amino acid-specific y+-system. Both mechanisms result in reduced NO production. ADMA levels are regulated by the interplay between the production by protein arginine methyltransferases (PRMTs), and the elimination by the metabolizing enzymes dimethylarginine dimethylaminohydrolase (DDAH) and, to a much lesser extent, by urinary excretion. However, as pointed out by the authors, numerous human studies have shown no beneficial effects of arginine supplementation, indicating a level of complexity for the regulation of ADMA levels that is not yet fully understood. The pioneering work by the authors themselves reveals a new mechanism that can explain some of these discrepancies. By showing that arginine directly inhibits DDAH in hepatic (HepG2) cells [3], they provide important information why arginine administration often fails to improve NO production. The knowledge about the cellular regulation of ADMA is constantly growing and will hopefully result in improved therapeutic strategies, especially for patients with vascular dysfunction due to impaired NO production.
|
|
| 3. |
- van Kuilenburg, André B P, et al.
(författare)
-
Clinical, biochemical and genetic findings in two siblings with a dihydropyrimidinase deficiency
- 2007
-
Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192 .- 1096-7206. ; 91:2, s. 157-164
-
Tidskriftsartikel (refereegranskat)abstract
- Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and it catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, respectively. To date, only nine individuals have been reported suffering from a complete DHP deficiency. We report two siblings presenting with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. One of the siblings had a severe delay in speech development and white matter abnormalities, whereas the other one was free of symptoms. Analysis of the DHP gene (DPYS) showed that both patients were compound heterozygous for the missense mutation 1078T>C (W360R) in exon 6 and a novel missense mutation 1235G>T (R412M) in exon 7. Heterologous expression of the mutant enzymes in Escherichia coli showed that both missense mutations resulted in a mutant DHP enzyme without residual activity. Analysis of the crystal structure of eukaryotic DHP from the yeast Saccharomyces kluyveri and the slime mold Dictyostelium discoideum suggests that the W360R and R412M mutations lead to structural instability of the enzyme which could potentially impair the assembly of the tetramer.
|
|
