A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes.
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.
Maeda
Shiro
S
Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan. smaeda@src.riken.jp
Kobayashi
Masa-aki
MA
Araki
Shin-ichi
S
Babazono
Tetsuya
T
Freedman
Barry I
BI
Bostrom
Meredith A
MA
Cooke
Jessica N
JN
Toyoda
Masao
M
Umezono
Tomoya
T
Tarnow
Lise
L
Hansen
Torben
T
Gaede
Peter
P
Jorsal
Anders
A
Ng
Daniel P K
DP
Ikeda
Minoru
M
Yanagimoto
Toru
T
Tsunoda
Tatsuhiko
T
Unoki
Hiroyuki
H
Kawai
Koichi
K
Imanishi
Masahito
M
Suzuki
Daisuke
D
Shin
Hyoung Doo
HD
Park
Kyong Soo
KS
Kashiwagi
Atsunori
A
Iwamoto
Yasuhiko
Y
Kaku
Kohei
K
Kawamori
Ryuzo
R
Parving
Hans-Henrik
HH
Bowden
Donald W
DW
Pedersen
Oluf
O
Nakamura
Yusuke
Y
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
D004247:DNA; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase