A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans.
BACKGROUND
Four linkage analyses have identified a region on chromosome 18q22-23 that appears to harbour a diabetic nephropathy (DN) susceptibility locus. A trinucleotide repeat sequence in exon 2 of the carnosinase gene (CNDP1) residing on 18q22.3 was subsequently associated with DN in European Caucasians and Arabs.


METHODS
We evaluated the role of the CNDP1 5 leucine/5 leucine (5-5) polymorphism (CNDP1 Mannheim) in diabetic end-stage renal disease (ESRD) susceptibility in 858 European Americans: 294 with type 2 DN-associated ESRD (DN-ESRD), 258 with diabetes mellitus (DM) lacking nephropathy and 306 healthy controls.


RESULTS
Subjects with DM lacking nephropathy were significantly more likely to be homozygous for the 5-leucine repeat CNDP1 genotype (5-5), compared with those with DN-ESRD (P=0.02). Healthy controls were also more likely to be homozygous for the 5-5 genotype, compared with those with DN-ESRD (P=0.008). No significant difference in 5-5 genotype frequency was observed between healthy controls and DM cases without nephropathy (P=0.74).


CONCLUSIONS
European Americans homozygous for the 5-5 leucine repeat polymorphism in the CNDP1 gene are at significantly reduced risk for developing diabetic ESRD. This replicates the CNDP1 gene association with DN that was initially detected in European Caucasians and in Arabs, and further demonstrates that the CNDP1 gene and carnosine pathway appear to play a role in susceptibility to DN.
Freedman
Barry I
BI
Department of Internal Medicine, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053, USA. bfreedma@wfubmc.edu
Hicks
Pamela J
PJ
Sale
Michele M
MM
Pierson
Eric D
ED
Langefeld
Carl D
CD
Rich
Stephen S
SS
Xu
Jianzhao
J
McDonough
Caitrin
C
Janssen
Bart
B
Yard
Benito A
BA
van der Woude
Fokko J
FJ
Bowden
Donald W
DW
D000328:Adult; D000368:Aged; D000483:Alleles; D002336:Carnosine / Q000502:physiology; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000208:ethnology* / Q000235:genetics*; D004150:Dipeptidases / Q000235:genetics*; D005060:Europe / Q000208:ethnology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000208:ethnology* / Q000235:genetics*; D007930:Leucine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D018911:Trinucleotide Repeats / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000208:ethnology / Q000235:genetics
D002336:Carnosine; D004150:Dipeptidases; C019673:aminoacyl-histidine dipeptidase; D007930:Leucine