Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan.
PLoS Genet. 2010 Feb 12;6(2):e1000842. doi: 10.1371/journal.pgen.1000842.
It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.
有人认为遗传易感性在糖尿病肾病的发病机制中起重要作用。对日本 2 型糖尿病患者基于基因的单核苷酸多态性（SNP）的大规模基因分型分析，鉴定出编码乙酰辅酶 A 羧化酶β（ACACB）的基因是糖尿病肾病易感性的候选基因；标志性 SNP 位于 ACACB 内含子 18（rs2268388：内含子 18 +4139 C>T，p=1.4x10(-6)，优势比=1.61，95%置信区间[CI]：1.33-1.96）。在包括原始研究在内的来自日本的 4 项、来自新加坡的 1 项、来自韩国的 1 项和来自欧洲的 2 项独立的 2 型糖尿病研究中，对该 SNP 与糖尿病肾病的相关性进行了检测。纳入了一项涉及欧洲 1 型糖尿病患者的病例对照研究。在 SNP rs2268388 中，T 等位基因在 2 型糖尿病和蛋白尿患者中的频率始终较高。荟萃分析显示，rs2268388 与日本 2 型糖尿病患者的蛋白尿显著相关（p=5.35x10(-8)，优势比=1.61，95%CI：1.35-1.91）。rs2268388 也与欧洲裔美国人的 2 型糖尿病相关终末期肾病（ESRD）相关（p=6x10(-4)，优势比=1.61，95%CI：1.22-2.13）。在 1 型糖尿病患者中，该 SNP 与肾病之间未检测到显著相关性。随后的体外功能分析显示，包括 rs2268388 在内的 29 个碱基对 DNA 片段在培养的人肾近端肾小管上皮细胞中具有显著的增强子活性。与疾病易感性等位基因（T）相对应的片段比主要等位基因具有更高的增强子活性。这些结果表明，ACACB 是 2 型糖尿病患者蛋白尿易感性的有力候选基因。
