ABSTRACT
OBJECTIVE: Mannose-binding lectin (MBL) is an essential component of the acute-phase immune response and may thus play a role in the pathogenesis of type 1 diabetes and diabetic nephropathy. The serum concentration of MBL is mainly genetically determined, and elevated concentrations have been associated with both type 1 diabetes and diabetic nephropathy. Previous genetic studies have not been conclusive due to the small number of patients and polymorphisms studied. We investigated whether MBL2 polymorphisms are associated with type 1 diabetes or diabetic nephropathy and whether patients with nephropathy have elevated MBL concentrations as indicated previously. Furthermore, we studied the association between MBL2 polymorphisms and MBL concentration. RESEARCH DESIGN AND METHODS: We genotyped 20 MBL2 single nucleotide polymorphisms (SNPs) in a large, well-characterized Finnish case-control sample consisting of 1,297 patients with type 1 diabetes with or without nephropathy and 701 nondiabetic individuals. The serum concentration of MBL was available for 1,064 patients. RESULTS: We found that 19 SNPs were associated with the MBL concentration (P = 3 x 10(-81)-7 x 10(-4)). MBL concentrations were higher in patients with macroalbuminuria compared with patients without nephropathy even when the patients were stratified by the MBL2 genotypic background in accordance with previous studies. However, no evidence of association between any of the SNPs or their haplotype combinations and type 1 diabetes or diabetic nephropathy was observed. CONCLUSIONS: Although most of the MBL2 SNPs studied were associated with the MBL concentration, no common variations (neither single SNPs nor their haplotype combinations) confer risk of type 1 diabetes or diabetic nephropathy.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/genetics , Mannose-Binding Lectin/genetics , Adult , Age of Onset , Albuminuria/genetics , Diabetes Mellitus, Type 1/complications , Female , Finland , Genotype , Humans , Kidney Failure, Chronic/genetics , Male , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Middle Aged , Polymorphism, Single Nucleotide , Reference Values , White People/geneticsABSTRACT
Vascular endothelial growth factor (VEGF) is a multifunctional cytokine originally described as an angiogenic factor. A number of reports have recently demonstrated that VEGF increases pancreatic islet survival after islet transplantation by stimulating angiogenesis and improving islet revascularization. Whether VEGF can protect from the autoimmune destruction of insulin-producing beta-cells that characterizes the development of type 1 diabetes is presently unknown. To clarify this issue, we studied the association of three polymorphisms of the promoter region of VEGF with type 1 diabetes in the Italian and the Finnish populations. The polymorphisms considered [C(-2578)A, G(-1190)A, and G(-1154)A] are known to modulate in vitro and in vivo VEGF expression. We found that VEGF promoter genotypes are associated with type 1 diabetes in both populations, but with different combinations. In Italian individuals, the -2578AA and -1190AA genotypes are associated with type 1 diabetes and accelerate its onset, while in Finnish individuals, -1154GG and -1190GG protect from type 1 diabetes and delay its onset. In conclusion, because the expected functional consequence of both genotype combinations is a reduced VEGF expression in diabetic patients, we propose a protective role of VEGF in the development of type 1 diabetes.
