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A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes
- Source :
- Maeda, S, Kobayashi, M, Araki, S, Babazono, T, Freedman, B I, Bostrom, M A, Cooke, J N, Toyoda, M, Umezono, T, Tarnow, L, Hansen, T, Gaede, P, Jorsal, A, Ng, D P K, Ikeda, M, Yanagimoto, T, Tsunoda, T, Unoki, H, Kawai, K, Imanishi, M, Suzuki, D, Shin, H D, Park, K S, Kashiwagi, A, Iwamoto, Y, Kaku, K, Kawamori, R, Parving, H-H, Bowden, D W, Pedersen, O & Nakamura, Y 2010, ' A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes ', P L o S Genetics, vol. 6, no. 2, pp. e1000842 . https://doi.org/10.1371/journal.pgen.1000842, PLoS Genetics, PLoS Genetics, Vol 6, Iss 2, p e1000842 (2010), Maeda, S, Kobayashi, M, Araki, S, Babazono, T, Freedman, B I, Bostrom, M A, Cooke, J N, Toyoda, M, Umezono, T, Tarnow, L, Hansen, T, Gaede, P, Jorsal, A, Ng, D P K, Ikeda, M, Yanagimoto, T, Tsunoda, T, Unoki, H, Kawai, K, Imanishi, M, Suzuki, D, Shin, H D, Park, K S, Kashiwagi, A, Iwamoto, Y, Kaku, K, Kawamori, R, Parving, H-H, Bowden, D W, Pedersen, O & Nakamura, Y 2010, ' A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes ' PLoS genetics, vol. 6, no. 2, pp. e1000842 . https://doi.org/10.1371/journal.pgen.1000842
- Publication Year :
- 2010
-
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.<br />Author Summary Although 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 SNPs from a Japanese SNP database, we show that the T-allele of ACACB rs2268388 is associated with diabetic nephropathy. We also show that the association is consistently observed in patients with type 2 diabetes and proteinuria across different ethnic groups, including populations of European descent. Because a DNA fragment corresponding to the disease susceptibility allele is shown to have higher enhancer activity, we hypothesize that the increase in the expression and/or activity of the encoded acetyl-coenzyme A carboxylase beta contributes to the development and progression of diabetic nephropathy. Our present analysis provides novel insight into the pathogenesis of diabetic nephropathy. This finding is important because diabetic nephropathy is a leading cause of end-stage renal disease and affects life expectancy in subjects with type 2 diabetes.
- Subjects :
- Cancer Research
Transcription, Genetic
030232 urology & nephrology
Genome-wide association study
Type 2 diabetes
Diabetic nephropathy
Cohort Studies
Kidney Tubules, Proximal
Mice
0302 clinical medicine
Diabetic Nephropathies
Base Pairing
Genetics (clinical)
Cells, Cultured
Genetics
ACACB
0303 health sciences
3. Good health
Proteinuria
Nephrology
Research Article
Adult
medicine.medical_specialty
lcsh:QH426-470
Molecular Sequence Data
Single-nucleotide polymorphism
Genetics and Genomics/Complex Traits
Biology
Polymorphism, Single Nucleotide
Gene Expression Regulation, Enzymologic
Nephropathy
03 medical and health sciences
Diabetes mellitus
Internal medicine
medicine
Animals
Humans
Genetic Predisposition to Disease
Diabetes and Endocrinology/Type 2 Diabetes
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Type 1 diabetes
Base Sequence
Gene Expression Profiling
Epithelial Cells
DNA
medicine.disease
lcsh:Genetics
Endocrinology
Diabetes Mellitus, Type 2
Case-Control Studies
Acetyl-CoA Carboxylase
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Maeda, S, Kobayashi, M, Araki, S, Babazono, T, Freedman, B I, Bostrom, M A, Cooke, J N, Toyoda, M, Umezono, T, Tarnow, L, Hansen, T, Gaede, P, Jorsal, A, Ng, D P K, Ikeda, M, Yanagimoto, T, Tsunoda, T, Unoki, H, Kawai, K, Imanishi, M, Suzuki, D, Shin, H D, Park, K S, Kashiwagi, A, Iwamoto, Y, Kaku, K, Kawamori, R, Parving, H-H, Bowden, D W, Pedersen, O & Nakamura, Y 2010, ' A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes ', P L o S Genetics, vol. 6, no. 2, pp. e1000842 . https://doi.org/10.1371/journal.pgen.1000842, PLoS Genetics, PLoS Genetics, Vol 6, Iss 2, p e1000842 (2010), Maeda, S, Kobayashi, M, Araki, S, Babazono, T, Freedman, B I, Bostrom, M A, Cooke, J N, Toyoda, M, Umezono, T, Tarnow, L, Hansen, T, Gaede, P, Jorsal, A, Ng, D P K, Ikeda, M, Yanagimoto, T, Tsunoda, T, Unoki, H, Kawai, K, Imanishi, M, Suzuki, D, Shin, H D, Park, K S, Kashiwagi, A, Iwamoto, Y, Kaku, K, Kawamori, R, Parving, H-H, Bowden, D W, Pedersen, O & Nakamura, Y 2010, ' A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes ' PLoS genetics, vol. 6, no. 2, pp. e1000842 . https://doi.org/10.1371/journal.pgen.1000842
- Accession number :
- edsair.doi.dedup.....271c5c32782150855e5481e953bbfb0d