Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT.
OBJECTIVE
Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria.


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 microg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 microg/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 microg/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.
De Cosmo
Salvatore
S
Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Motterlini
Nicola
N
Prudente
Sabrina
S
Pellegrini
Fabio
F
Trevisan
Roberto
R
Bossi
Antonio
A
Remuzzi
Giuseppe
G
Trischitta
Vincenzo
V
Ruggenenti
Piero
P
D000328:Adult; D000368:Aged; D000409:Alanine; D000419:Albuminuria / Q000150:complications / Q000453:epidemiology* / Q000209:etiology* / Q000235:genetics; D000483:Alleles; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D048909:Diabetes Complications / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011392:Proline; D011446:Prospective Studies; D012107:Research Design; D012307:Risk Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D047495:PPAR gamma; D011392:Proline; D000409:Alanine