Wolford J K, Yeatts K A, Red Eagle A R, Nelson R G, Knowler W C, Hanson R L
Translational Genomics Research Institute, Diabetes Research Unit, Phoenix, AZ 85004, USA.
Diabet Med. 2006 Apr;23(4):367-76. doi: 10.1111/j.1464-5491.2006.01834.x.
The aldose reductase gene (AKR1B1) is a strong candidate for diabetic nephropathy, and the T allele at rs759853 and the Z-2 allele at an [AC]n microsatellite are associated with diabetic kidney disease in some populations. As AKR1B1 is located on 7q35, where we have previously reported linkage to diabetic nephropathy in Pima Indians, this study examined the association of AKR1B1 variants with diabetic nephropathy in this population.
AKR1B1 variants were identified by sequencing and genotyped using allelic discrimination and pyrosequencing. Genotype distributions were compared between 107 cases with diabetic end-stage renal disease and 108 control subjects with diabetes for > or = 10 years and no evidence of nephropathy, and between 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships.
We identified 11 AKR1B1 single nucleotide polymorphisms (SNPs) and the [AC]n microsatellite polymorphism. Three SNPs were rare and two were in 100% genotypic concordance; thus, eight polymorphisms were genotyped. No variant was associated with diabetic kidney disease in the case-control or family-based study. For example, the T allele at rs759853 had an allele frequency of 0.165 in cases and 0.171 in control subjects (OR = 0.96, 95% CI, 0.57-1.59, P = 0.86); in the family study its frequency was 0.140 and 0.169 in affected and unaffected individuals, respectively (OR = 0.90, 95% CI, 0.53-1.54 P = 0.71). Corresponding values for the Z-2 allele at the [AC]n microsatellite were OR = 1.09 (95% CI 0.72-1.66, P = 0.67) and OR = 1.25 (95% CI 0.81-1.95, P = 0.31) in the case-control and family studies, respectively.
Common AKR1B1 polymorphisms are unlikely to be major determinants of diabetic nephropathy in this population.
醛糖还原酶基因（AKR1B1）是糖尿病肾病的一个强有力候选基因，rs759853位点的T等位基因以及[AC]n微卫星的Z - 2等位基因在一些人群中与糖尿病肾病相关。由于AKR1B1位于7q35，我们之前报道过皮马印第安人该区域与糖尿病肾病存在连锁关系，本研究检测了该人群中AKR1B1变异与糖尿病肾病的相关性。
通过测序鉴定AKR1B1变异，并使用等位基因鉴别和焦磷酸测序进行基因分型。比较了107例糖尿病终末期肾病患者与108例患糖尿病≥10年且无肾病证据的对照者之间的基因型分布，以及在一个包含257个同胞对的家系研究中141例肾病患者与416例无大量蛋白尿个体之间的基因型分布。
我们鉴定出11个AKR1B1单核苷酸多态性（SNP）以及[AC]n微卫星多态性。3个SNP罕见，2个处于100%基因型一致性；因此，对8个多态性进行了基因分型。在病例对照研究或家系研究中，没有变异与糖尿病肾病相关。例如，rs759853位点的T等位基因在病例组中的等位基因频率为0.165，在对照组中为0.171（比值比 = 0.96，95%可信区间，0.57 - 1.59，P = 0.86）；在家系研究中，其在患病个体和未患病个体中的频率分别为0.140和0.169（比值比 = 0.90，95%可信区间，0.53 - 1.54，P = 0.71）。在病例对照研究和家系研究中，[AC]n微卫星Z - 2等位基因的相应比值比分别为1.09（95%可信区间0.72 - 1.66，P = 0.67）和1.25（95%可信区间0.81 - 1.95，P = 0.31）。
常见的AKR1B1多态性不太可能是该人群中糖尿病肾病的主要决定因素。
