A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus.
OBJECTIVE
Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD).


METHODS
In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥ 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation.


RESULTS
The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03).


CONCLUSIONS
CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.
Alkhalaf
A
A
Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. a.alkhalaf@int.umcg.nl
Bakker
S J L
SJ
Bilo
H J G
HJ
Gans
R O B
RO
Navis
G J
GJ
Postmus
D
D
Forsblom
C
C
Groop
P H
PH
Vionnet
N
N
Hadjadj
S
S
Marre
M
M
Parving
H H
HH
Rossing
P
P
Tarnow
L
L
D000328:Adult; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D004150:Dipeptidases / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011379:Prognosis; D016019:Survival Analysis; D044465:White People / Q000235:genetics
C522928:CNDP1 protein, human; D004150:Dipeptidases