McDonough Caitrin W, Hicks Pamela J, Lu Lingyi, Langefeld Carl D, Freedman Barry I, Bowden Donald W
Center for Diabetes Research, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Hum Genet. 2009 Aug;126(2):265-75. doi: 10.1007/s00439-009-0667-0. Epub 2009 Apr 17.
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.
四项针对糖尿病肾病的全基因组连锁扫描已将易感基因座定位到肌肽酶基因CNDP1和CNDP2所在区域的18号染色体q22.3 - 23。在欧洲人和欧裔美国人中，CNDP1与糖尿病肾病相关，但在非裔美国人中并非如此。纯合子携带五个三核苷酸重复等位基因（5L；D18S880）的个体可免受糖尿病肾病的影响。我们在非裔美国人和欧裔美国人的DNA样本中对CNDP1和CNDP2的外显子、启动子及3'非翻译区进行测序后，鉴定出64个变异体。在对其中44个变异体进行扫描后，我们对1025例患有2型糖尿病（DM）相关终末期肾病（ESRD）的非裔美国人病例和1064例非糖尿病非肾病的非裔美国人对照进行了12个单核苷酸多态性（SNP）和D18S880的广泛基因分型，以评估肌肽酶基因是否影响非裔美国人患DM - ESRD的风险。观察到与DM - ESRD相关的证据有2个SNP：rs6566810和rs4892247；3个双标记单倍型：rs6566810和rs17089362、rs17089362和rs890336以及rs890334和rs12717111（全局经验P值分别为0.0034、0.0275和0.0002），以及3个三标记单倍型：rs6566810、rs17089362和rs890336；rs890335、rs890334和rs12717111；以及rs890334、rs12717111和D18S880（全局经验P值分别为0.0074、1.5E - 05和0.0032）。风险单倍型（rs6566810、rs17089362 [A,T]以及rs6566810、rs17089362、rs890336 [A,T,C]）在非5L - 5L组的非裔美国人中与DM - ESRD的关联最为强烈。肌肽酶基因中的变异体似乎在非裔美国人中对糖尿病肾病易感性有影响。CNDP1中5L - 5L纯合子所提供的对糖尿病肾病的保护作用可能被CNDP1和CNDP2中其他风险单倍型的效应所掩盖。
