ABSTRACT
AIMS: We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-beta 1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes. METHODS: We conducted a large case-control study using cases with Type 1 diabetes and clinical nephropathy. Controls were Type 1 diabetic subjects who have been injecting insulin for at least 50 years and have extremely low risk of nephropathy. Genotyping was by polymerase chain reaction with sequence-specific primers. RESULTS: There was a significant difference in the frequency of the TGF-beta 1 codon 10 genotypes in the diabetic nephropathy group (n = 420) when compared with the controls (n = 410, P = 0.007). There were no significant differences when the frequencies of the TGF-beta1 codons 25 and 263 genotypes in the diabetic nephropathy group were compared with the control group. CONCLUSIONS: In our study the TGF-beta 1 codon 10 polymorphism is associated with nephropathy in Type 1 diabetes and variation in this gene may contribute to the genetic predisposition to this complication in Type 1 diabetes.
Subject(s)
Codon/genetics , Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/genetics , Genetic Predisposition to Disease/genetics , Transforming Growth Factor beta/genetics , Adult , Case-Control Studies , Female , Genotype , Humans , Male , Polymorphism, Genetic , Transforming Growth Factor beta1ABSTRACT
AIMS/HYPOTHESIS: Susceptibility to diabetic nephropathy in subjects with Type 1 diabetes is mainly genetically determined. Excess cardiovascular risk associated with diabetes is overwhelmingly concentrated in patients with nephropathy. Endothelial dysfunction is a feature of cardiovascular disease, hypertension, dyslipidaemia and smoking, all of which are associated with diabetic nephropathy. Nitric oxide regulates endothelial function and so genes encoding nitric oxide synthases could confer susceptibility to nephropathy. Recently positive associations have been reported. We examined polymorphisms within NOS3 and NOS2A, the genes encoding endothelial- and inducible nitric oxide synthase, for association with nephropathy. METHODS: Large case-control studies of patients with Type 1 diabetes and overt nephropathy who had hypertension and diabetic retinopathy. The control group comprised Type 1 diabetic subjects who have been on insulin for 50 or more years and have an extremely low risk of nephropathy. Genotyping was by PCR and agarose- or automated polyacrylamide gel electrophoresis using fluorescence-labelled primers. RESULTS: NOS3 intron 4 genotype frequencies (n=860: 464 cases, 396 control subjects) were 2.6%, 23.3%, 74.1% and 2.3%, 22.7%, 75.0% for aa, ab and bb genotypes; p=0.935. NOS2A promoter genotype frequencies (n=715: 358 cases, 357 control subjects) were 0.3%, 16.8%, 83.0% and 0.3% 17.6% and 82.1% for +/+, +/- and -/- genotypes (p=0.952). CONCLUSION/INTERPRETATION: In our cohort of Caucasian subjects with Type 1 diabetes there is no association between either of the polymorphisms studied and diabetic nephropathy. The previous suggestion from smaller studies that the intron 4 polymorphism in NOS3 could play a role in susceptibility to the disease is not confirmed.
Subject(s)
Diabetic Nephropathies/enzymology , Diabetic Nephropathies/genetics , Nitric Oxide Synthase/genetics , Polymorphism, Genetic/genetics , Alleles , DNA/genetics , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/genetics , Electrophoresis, Agar Gel , Electrophoresis, Polyacrylamide Gel , Gene Frequency , Genotype , Humans , Introns/genetics , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Reverse Transcriptase Polymerase Chain ReactionSubject(s)
Anticoagulants/adverse effects , Dalteparin/adverse effects , Diabetes Mellitus, Type 1/complications , Fibrinolytic Agents/adverse effects , Heparin, Low-Molecular-Weight/adverse effects , Hyperkalemia/chemically induced , Acute Disease , Anticoagulants/administration & dosage , Dalteparin/administration & dosage , Female , Fibrinolytic Agents/administration & dosage , Follow-Up Studies , Heparin, Low-Molecular-Weight/administration & dosage , Humans , Hyperkalemia/drug therapy , Middle Aged , Polystyrenes/therapeutic use , Thrombophlebitis/drug therapy , Time FactorsABSTRACT
Diabetic nephropathy can develop in up to one-third of patients with type 1 diabetes and approximately 25% of patients with type 2 diabetes. This complication is important as it not only leads to renal failure but is associated with a high risk of coronary artery disease and other vascular complications. Although hyperglycaemia is necessary for the development of diabetic nephropathy, it is not sufficient, genetic factors also being important. This is evidenced by studies showing that only a subgroup of patients are at risk of nephropathy and that nephropathy clusters in families. The genes involved in susceptibility to diabetic nephropathy have yet to be identified. Most studies to date have been case-control in design, and there have been conflicting results. Genes suggested as having a role include those encoding angiotensin-1 converting enzyme, apolipoprotein E, heparan sulphate and aldose reductase. In order to clarify the role of these and other candidate genes in nephropathy, association studies in families are necessary. Because of the large number required, this will require international collaboration. A genetic marker for nephropathy would enable the earlier detection of this complication, thus facilitating screening and targeted intervention. An understanding of the role of susceptibility genes will ultimately allow the development of novel therapeutic strategies.
