ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy

Diabetes. 2013 Oct;62(10):3599-609. doi: 10.2337/db13-0530. Epub 2013 Jun 3.


In patients with diabetes, impaired ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) proteolysis of highly thrombogenic von Willebrand factor (VWF) multimers may accelerate renal and cardiovascular complications. Restoring physiological VWF handling might contribute to ACE inhibitors' (ACEi) reno- and cardioprotective effects. To assess how Pro618Ala ADAMTS13 variants and related proteolytic activity interact with ACEi therapy in predicting renal and cardiovascular complications, we genotyped 1,163 normoalbuminuric type 2 diabetic patients from BErgamo NEphrologic DIabetes Complications Trial (BENEDICT). Interaction between Pro618Ala and ACEi was significant in predicting both renal and combined renal and cardiovascular events. The risk for renal or combined events versus reference Ala carriers on ACEi progressively increased from Pro/Pro homozygotes on ACEi (hazard ratio 2.80 [95% CI 0.849-9.216] and 1.58 [0.737-3.379], respectively) to Pro/Pro homozygotes on non-ACEi (4.77 [1.484-15.357] and 1.99 [0.944-4.187]) to Ala carriers on non-ACEi (8.50 [2.416-29.962] and 4.00 [1.739-9.207]). In a substudy, serum ADAMTS13 activity was significantly lower in Ala carriers than in Pro/Pro homozygotes and in case subjects with renal, cardiovascular, or combined events than in diabetic control subjects without events. ADAMTS13 activity significantly and negatively correlated with all outcomes. In patients with diabetes, ADAMTS13 618Ala variant associated with less proteolytic activity, higher risk of chronic complications, and better response to ACEi therapy. Screening for Pro618Ala polymorphism may help identify patients with diabetes at highest risk who may benefit the most from early reno- and cardioprotective therapy.

Trial registration: NCT00235014.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / blood*
  • ADAMTS13 Protein
  • Aged
  • Alanine
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Biomarkers / blood
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / prevention & control
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetic Angiopathies / blood*
  • Diabetic Angiopathies / genetics
  • Diabetic Angiopathies / prevention & control
  • Diabetic Nephropathies / blood*
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / prevention & control
  • Disease Progression
  • Female
  • Genotype
  • Humans
  • Kidney Failure, Chronic / blood
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Proline
  • Proteolysis
  • Risk Assessment
  • Risk Factors
  • von Willebrand Factor / genetics


  • Angiotensin-Converting Enzyme Inhibitors
  • Biomarkers
  • von Willebrand Factor
  • Proline
  • ADAM Proteins
  • ADAMTS13 Protein
  • ADAMTS13 protein, human
  • Alanine

Associated data