A Single Nucleotide Polymorphism within the Acetyl-Coenzyme A Carboxylase Beta Gene Is Associated with Proteinuria in Patients with Type 2 Diabetes

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.

TheACACBgene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis

“…5 A recent study revealed that the T allele is associated with DM-related nephropathy. 4 A similar result was also observed by Tang et al 6 However, a recent meta-analysis on the role of the ACACB SNP rs2268388 in the development of DN have shown conflicting results (OR ¼ 0.83; 95% CI ¼ 0.62-1.11). 7 The exact relationship between the ACACB SNP rs2268388 and DN susceptibility is not well established.…”

“…3 Relative to the C allele, a 29-bp DNA fragment containing the T allele in intron 18 of ACACB gene (rs2268388; intron-18 +4 139 C4T) demonstrated greater enhancer activity in cultured human renal proximal tubular epithelial cells, indicating higher ACACB expression in risk allele carriers. 4 Therefore, rs2268388 could contribute to the regulation of metabolism, alterations in lipids, and adiposity. 5 A recent study revealed that the T allele is associated with DM-related nephropathy.…”

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

“…(FRMD3), -cysteinyl-tRNA synthetase (CARS), -plasmacytoma variant translocation 1 (PVT1), -engulfment and cell motility 1 (ELMO1), -carnosinase 1 (CNDP1), -carnosinase 2 (CNDP2), -endothelial nitric oxide synthase (eNOS), -acetyl-coenzyme A carboxylase beta (ACACB), -protein kinase C beta 1 (PRKCB1), -LIM domain kinase 2 (LIMK2), -Sfi1 homolog, -spindle assembly associated (SFI1), and -ribosomal protein S12 (RPS12) [99][100][101][102].…”

“…Similar to genetic pathways in the development of CAD, it can be theorized that some T2D mechanistic pathways may share a common pathogenesis with susceptibility to DN. For example, a single nucleotide polymorphism in the ACACB gene is strongly associated with albuminuria and advanced CKD in Asians and EAs [101,103]. The gene product is the acetyl-CoA carboxylase beta enzyme, which is important in fatty acid oxidation.…”

Lipotoxicity in Diabetic Nephropathy

“…A single variant of the enzyme controlling FFA oxidation (the ACACB gene) has recently been shown to be robustly associated with T2DN in numerous cohorts of individuals from different genetic backgrounds (5,6). The ACACB minor allele likely mediates this risk through the canonical toxic cytosolic FFA accumulation as a consequence of enhanced ACACB-mediated inhibition of CPT1 and reduced FA oxidation.…”