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.
McDonough
Caitrin W
CW
Center for Diabetes Research, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Hicks
Pamela J
PJ
Lu
Lingyi
L
Langefeld
Carl D
CD
Freedman
Barry I
BI
Bowden
Donald W
DW
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