title: 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 = 1.4x10(-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.
authors.affiliation: Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan. smaeda@src.riken.jp
authors.forename: Shiro
authors.initials: S
authors.lastname: Maeda
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Kobayashi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Babazono
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Bostrom
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Cooke
authors.forename: Masao
authors.initials: M
authors.lastname: Toyoda
authors.forename: Tomoya
authors.initials: T
authors.lastname: Umezono
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Peter
authors.initials: P
authors.lastname: Gaede
authors.forename: Anders
authors.initials: A
authors.lastname: Jorsal
authors.forename: Daniel P K
authors.initials: DP
authors.lastname: Ng
authors.forename: Minoru
authors.initials: M
authors.lastname: Ikeda
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagimoto
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Unoki
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Masahito
authors.initials: M
authors.lastname: Imanishi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Suzuki
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Kawamori
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000328:Adult; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000150:complications / Q000201:enzymology / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011507:Proteinuria / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004247:DNA; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase