Impact of the PPAR-γ2 Pro12Ala Polymorphism and ACE Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: Evidence From BENEDICT
- Salvatore De Cosmo1,
- Nicola Motterlini2,
- Sabrina Prudente3,4,
- Fabio Pellegrini5,
- Roberto Trevisan6,
- Antonio Bossi7,
- Giuseppe Remuzzi2,8,
- Vincenzo Trischitta3,4,9,
- Piero Ruggenenti2,8 and
- on behalf of the BENEDICT Study Group*
- 1Unit of Endocrinology, IRCCS “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy;
- 2Clinical Research Center for Rare Diseases “Aldo & Cele Daccò,” Mario Negri Institute for Pharmacological Research, Bergamo, Italy;
- 3Research Unit of Diabetes and Endocrine Diseases, IRCCS “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy;
- 4IRCCS “Casa Sollievo della Sofferenza,” Mendel Institute, Rome, Italy;
- 5Unit of Biostatistics, IRCCS “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy;
- 6Unit of Diabetology, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy;
- 7Unit of Diabetology, Treviglio Hospital, Treviglio, Italy;
- 8Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy;
- 9Department of Medical Pathophysiology, “Sapienza” University, Rome, Italy.
- Corresponding author: Giuseppe Remuzzi, gremuzzi{at}marionegri.it.
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V.T. and P.R. equally supervised the study.
Abstract
OBJECTIVE Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator–activated receptor-γ2 (PPAR-γ2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria.
RESEARCH DESIGN AND METHODS Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)—a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20–200 μg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 μg/min at inclusion.
RESULTS Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1–51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21–0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 ± 9.1 vs. 10.5 ± 24.9 μg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29–0.72]; P < 0.001).
CONCLUSIONS In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy.
Footnotes
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*A complete list of the members of the BENEDICT Study Organization can be found in the appendix.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received March 18, 2009.
- Accepted August 1, 2009.
- © 2009 American Diabetes Association
