Abstract
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 = 1.4×10−6, 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 = 5.35×10−8, 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 = 6×10−4, 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.
Highlights
Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) in Western countries [1] and in Japan [2]
Cumulative epidemiological findings have suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy, no gene conferring susceptibility to diabetic nephropathy has been definitively identified
In a large-scale association study of 1,312 Japanese subjects with type 2 diabetes using single nucleotide polymorphisms (SNPs) from a Japanese SNP database, we show that the T-allele of acetyl-coenzyme A carboxylase beta (ACACB) rs2268388 is associated with diabetic nephropathy
Summary
Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) in Western countries [1] and in Japan [2]. Susceptibility to diabetic nephropathy appears to be determined by multiple genetic and environmental risk factors, and genetic susceptibility plays an important role in its development and progression [3,4]. Both candidate gene approaches and genome-wide linkage analyses have suggested several candidate genes with potential impact on diabetic nephropathy. Conducted GWAS in a population of European descent identified 4 distinct loci associated with diabetic nephropathy in type 1 diabetes. Two of these loci were replicated in a population of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohorts [11]
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