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Eero Lindholm

Candidate Genes for Late Diabetic Complications

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The new WHO criteria for classification of diabetes takes into account also clinical stages dividing the diabetic patients into noninsulin requiring (NIR), insulin requiring for control (IRC) and insulin requiring for survival (IRS) subgroups. Diabetic complications are the result of chronically elevated blood glucose. Genetic factors are believed to play role in pathogenesis of diabetic complications.

The aim of this study was to

1) To test the usefulness of the new WHO criteria for clinical staging of diabetes in the characterization of diabetic patients.

2) To test a putative association between late diabetic complications and candidate gene polymorphisms.

In study I we could show that the WHO clinical staging of diabetes could discriminate between clinically meaningful subgroups. The IRC patients represented a group with more severe diabetes than acknowledged in the etiological classification with high frequency of diabetic complications. In study II we demonstrated that polymorphisms in the UCP1-3 genes did not play a major role in the development of micro- or macroalbuminuria in Scandinavian diabetic patients. In study III we showed that a polymorphism in the MHC class II transactivator gene (MHC2TA) was associated with cardiovascular mortality and predictors of cardiovascular mortality, microalbuminuria and metabolic syndrome. In study IV and V we showed that polymorphisms in the LTA, TNF and AGER genes were associated with diabetic complications. The association was complex and dependent on the HLA-DQB1 genotypes, with partly different alleles conferring susceptibility in type 1 and type 2 diabetic patients. We cannot exclude that these genes are a part of a large haplotype block that also includes HLA-DQB1 risk genotypes.

Although this study revealed several associations with putative candidate gene polymorphisms and diabetic complications, the studied polymorphisms can only explain part of the genetic riskfactors for diabetic complications. More studies are needed to enable mapping of the susceptibility genes for diabetic complications. Revealing the genetic riskfactors could help us to identify the patients at risk and understand the pathogenesis of diabetic complications and making it possible to find novel treatments for diabetic complications.

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