The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans.
Four genome wide linkage scans for diabetic nephropathy have mapped susceptibility loci to chromosome 18q22.3-23 in the region of the carnosinase genes, CNDP1 and CNDP2. CNDP1 has been associated with diabetic nephropathy in Europeans and European Americans, but not African-Americans. Individuals homozygous for a five tri-nucleotide repeat allele (5L; D18S880) are protected from diabetic nephropathy. We identified 64 variants after sequencing the exons, promoter, and 3' UTR of CNDP1 and CNDP2 in African-American and European American DNA samples. After scanning 44 of these variants, extensive genotyping of 12 SNPs and D18S880 was performed in 1,025 African-American cases with type 2 diabetes (DM)-associated end-stage renal disease (ESRD) and 1,064 African-American non-diabetic non-nephropathy controls to assess whether the carnosinase genes influence risk for DM-ESRD in African-Americans. Evidence of association with DM-ESRD was seen with 2 SNPs: rs6566810 and rs4892247; 3 two-marker haplotypes: rs6566810 and rs17089362, rs17089362 and rs890336, and rs890334 and rs12717111 (global empirical P = 0.0034, 0.0275, and 0.0002, respectively) and 3 three-marker haplotypes: rs6566810, rs17089362, and rs890336; rs890335, rs890334, and rs12717111; and rs890334, rs12717111, and D18S880 (global empirical P = 0.0074, 1.5E-05, and 0.0032, respectively). The risk haplotypes (rs6566810, rs17089362 [A,T] and rs6566810, rs17089362, rs890336 [A,T,C]) were most strongly associated with DM-ESRD among African-Americans in the non 5L-5L group. Variants in the carnosinase genes appear to contribute to diabetic nephropathy susceptibility in African-Americans. Protection from diabetic nephropathy afforded by 5L-5L homozygosity in CNDP1 may be masked by the effects of additional risk haplotypes in CNDP1 and CNDP2.
Center for Diabetes Research, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Caitrin W
CW
McDonough
Pamela J
PJ
Hicks
Lingyi
L
Lu
Carl D
CD
Langefeld
Barry I
BI
Freedman
Donald W
DW
Bowden
D000328:Adult; D001741:Black or African American; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000235:genetics*; D004150:Dipeptidases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D016678:Genome; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
D004150:Dipeptidases; C019673:aminoacyl-histidine dipeptidase