A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes

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Shiro Maeda, Masa-aki Kobayashi, Shin-ichi Araki, Tetsuya Babazono, Barry I Freedman, Meredith A Bostrom, Jessica N Cooke, Masao Toyoda, Tomoya Umezono, Lise Tarnow, Torben Hansen, Peter Gaede, Anders Jorsal, Daniel P K Ng, Minoru Ikeda, Toru Yanagimoto, Tatsuhiko Tsunoda, Hiroyuki Unoki, Koichi Kawai, Masahito Imanishi & 11 others Daisuke Suzuki, Hyoung Doo Shin, Kyong Soo Park, Atsunori Kashiwagi, Yasuhiko Iwamoto, Kohei Kaku, Ryuzo Kawamori, Hans-Henrik Parving, Donald W Bowden, Oluf Pedersen, Yusuke Nakamura

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.
Original languageEnglish
JournalP L o S Genetics
Volume6
Issue number2
Pages (from-to)e1000842
ISSN1553-7390
DOIs
Publication statusPublished - 1 Jan 2010

    Research areas

  • Acetyl-CoA Carboxylase, Adult, Animals, Base Pairing, Base Sequence, Case-Control Studies, Cells, Cultured, Cohort Studies, DNA, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Tubules, Proximal, Mice, Molecular Sequence Data, Polymorphism, Single Nucleotide, Proteinuria, Transcription, Genetic

ID: 34163246