title: ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy.
abstract: 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.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Rurali
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Antonietta
authors.initials: A
authors.lastname: Chianca
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.forename: Federica
authors.initials: F
authors.lastname: Banterla
authors.forename: Miriam
authors.initials: M
authors.lastname: Galbusera
authors.forename: Giulia
authors.initials: G
authors.lastname: Gherardi
authors.forename: Sara
authors.initials: S
authors.lastname: Gastoldi
authors.forename: Aneliya
authors.initials: A
authors.lastname: Parvanova
authors.forename: Ilian
authors.initials: I
authors.lastname: Iliev
authors.forename: Antonio
authors.initials: A
authors.lastname: Bossi
authors.forename: Carolina
authors.initials: C
authors.lastname: Haefliger
authors.forename: Roberto
authors.initials: R
authors.lastname: Trevisan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
mesh_terms: D051722:ADAM Proteins / Q000097:blood*; D000071120:ADAMTS13 Protein; D000368:Aged; D000409:Alanine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D003925:Diabetic Angiopathies / Q000097:blood* / Q000235:genetics / Q000517:prevention & control; D003928:Diabetic Nephropathies / Q000097:blood* / Q000235:genetics / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011392:Proline; D059748:Proteolysis; D018570:Risk Assessment; D012307:Risk Factors; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D014841:von Willebrand Factor; D011392:Proline; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D000409:Alanine