The role of PC-1 and ACE genes in diabetic nephropathy in type 1 diabetic patients: evidence for a polygenic control of kidney disease progression.
BACKGROUND
The DD genotype of the ACE gene predisposes to faster diabetic nephropathy (DN) progression but its role in DN development is more controversial. We reported previously, in type 1 diabetic patients, an association between faster DN progression and the PC-1 gene Q121 variant, which associates with insulin resistance in non-diabetic subjects. We investigated here whether the combination of the ACE DD genotype and the PC-1 Q121 variant predicts the development and/or progression of DN in type 1 diabetic patients.


METHODS
Type 1 diabetic patients either with (n=159) or without (n=122) nephropathy were evaluated in a cross-sectional study. DN was defined as the presence of microalbuminuria or persistent proteinuria in a subject with more than 10-year duration of disease and concomitant diabetic retinopathy, and with no evidence of heart failure or other renal disease. Seventy-five (47 male/28 female) type 1 diabetic patients with nephropathy in whom retrospective information with repeated measurements of serum creatinine was available, were analysed in a longitudinal study.


RESULTS
No association of the PC-1 Q121 variant and the ACE D/D genotype with DN development was observed. However, the ACE DD genotype and the PC-1 Q121 variant were associated, both independently (P=0.02 and P=0.025, respectively) or in combination (P=0.02), with a faster rate of glomerular filtration rate decline. An interaction (P=0.03) was observed between the two genes in increasing the individual patient's risk of being a fast progressor.


CONCLUSIONS
Our data suggest that, in type 1 diabetic patients, the ACE and the PC-1 genes interact in increasing the individual risk of having a faster DN progression.
De Cosmo
Salvatore
S
Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza San Giovanni Rotondo (FG), Italy. endocrinologia@operapadrepio.it
Miscio
Giuseppe
G
Zucaro
Luigi
L
Margaglione
Maurizio
M
Argiolas
Alessandra
A
Thomas
Stephen
S
Piras
Giampiero
G
Trevisan
Roberto
R
Perin
Paolo Cavallo
PC
Bacci
Simonetta
S
Frittitta
Lucia
L
Pizzuti
Antonio
A
Tassi
Vittorio
V
Di Minno
Giovanni
G
Viberti
Giancarlo
G
Trischitta
Vincenzo
V
D000328:Adult; D017668:Age of Onset; D000419:Albuminuria; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D002784:Cholesterol; D003404:Creatinine; D006442:Glycated Hemoglobin; D007703:Peptidyl-Dipeptidase A; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D014280:Triglycerides; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1