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Title: ADAMTS13 polymorphisms : role in predicting renal and cardiovascular events in type 2 diabetes and response to therapy
Author: Rurali, Erica
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2013
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In diabetics, impaired ADAMTS13 proteolysis of highly-thrombogenic VWF multimers may accelerate renal and cardiovascular complications, that are major causes of illness and death in these patients. Restoring physiological VWF handling might contribute to ACE inhibitors (ACEi) reno- and cardioprotective effects. In this thesis is presented a study on the 1,163 normoalbuminuric type 2 diabetics from the BENEDICT phase A trial assessed to evaluate the interaction of the common nonsynonymous ADAMTS13 polymorphisms associated with impaired protease activity levels with ACEi therapy in predicting renal and cardiovascular complications. In this population the p.Pr0618Ala ADAMTS13 polymorphism was a major independent predictor of renal and cardiovascular events as well as of reno- and cardioprotective effects of ACEi therapy. Ala carriers showed the highest risk of events and, at the same time, had the largest benefit from ACEi therapy. Excess risk of events appeared to be associated with defective ADAMTS 13 activity. Indeed, in a sub-study on the same population, the 618Ala variant associated with less proteolytic activity, higher risk of chronic complications and better response to ACEi therapy. Thus, p.Pr0618Ala screening may help identifying diabetics at highest risk who may benefit the most from early reno- and cardioprotective therapy. Furthermore, among all ACEi treated microalbuminuric diabetics of the BENEDICT phase B, Ala carriers had lower risk of progression to macroalbuminuria and also higher risk of regression to normoalbuminuria. Thus, ACEi appears to be renoprotective both in the context of prevention, and as a treatment to ameliorate renal function. As a final evaluation, a genetic screening study on a third COhOli of diabetics with different extents of renal damage, revealed a higher prevalence of ADAMTS13 mutations in patients with severe nephropathy in respect to those without, sustaining the role of ADAMTS13 defects in diabetic nephropathy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available