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RISS 인기검색어
- 검색키워드
- 저자 : Barry I. Freedman (검색결과 3 건)
- 무료
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Maeda, Shiro,Kobayashi, Masa-aki,Araki, Shin-ichi,Babazono, Tetsuya,Freedman, Barry I.,Bostrom, Meredith A.,Cooke, Jessica N.,Toyoda, Masao,Umezono, Tomoya,Tarnow, Lise,Hansen, Torben,Gaede, Peter,Jor Public Library of Science 2010 PLoS genetics Vol.6 No.2
<▼1><P>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 (<I>ACACB</I>) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of <I>ACACB</I> (rs2268388: intron 18 +4139 C > T, p = 1.4×10<SUP>−6</SUP>, 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<SUP>−8</SUP>, 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<SUP>−4</SUP>, 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 <I>in vitro</I> 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 <I>ACACB</I> is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.</P></▼1><▼2><P><B>Author Summary</B></P><P>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 <I>ACACB</I> 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.</P></▼2>
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Freedman, Barry I,Bowden, Donald W,Ziegler, Julie T,Langefeld, Carl D,Lehtinen, Allison B,Rudock, Megan E,Lenchik, Leon,Hruska, Keith A,Register, Thomas C,Carr, J Jeffrey Mary Ann Liebert, Inc 2009 Journal of bone and mineral research Vol.24 No.10
<P>Inverse relationships have been observed between BMD and vascular calcification (VC), suggesting an underlying metabolic pathway linking these processes. Bone morphogenetic proteins (BMPs) are potential candidate genes that may mediate this relationship. Four single nucleotide polymorphisms (SNPs) in the BMP2 gene, 2 SNPs in BMP4, and 16 SNPs in BMP7 were tested for association with measures of VC using CT (coronary and carotid arteries, abdominal aorta), and BMD was measured using DXA (lumbar spine, hip, and distal radius) and quantitative CT (QCT; thoracic and lumbar spine) in 920 European Americans from 374 Diabetes Heart Study families: 762 with type 2 diabetes. Variance components quantitative trait locus association analysis was computed using SOLAR software, and a bivariate principal component analysis (PCA) assessed for genetic relationships between BMD and VC. Association was observed between several measures of BMD and BMP7 rs17404303 (thoracic spine QCT p = 0.03; lumbar spine QCT p = 0.02; hip DXA p = 0.06, dominant models). In addition, 6 of 16 BMP7 SNPs showed significant and opposing effects on the bivariate PCA for VC and BMD (two-sided exact test, p = 0.0143). Polymorphisms in BMP7 are associated with inverse relationships between bone mineralization and VC in the coronary, carotid, and abdominal aorta in a diabetes-enriched cohort of European Americans.</P>
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Megan E. Rudock,Amanda. J. Cox,Julie T. Ziegler,Allison B. Lehtinen,Jessica J. Connelly,Barry I. Freedman,J. Jeffrey Carr,Elizabeth R. Hauser,Benjamin D. Horne,Donald W. Bowden 한국유전학회 2011 Genes & Genomics Vol.33 No.5
All manifestations of cardiovascular disease (CVD) are substantially more common in patients with type 2 diabetes mellitus (T2DM) than in non-diabetic individuals. The current study evaluated KALRN, a gene previously linked to CVD, as a contributor to CVD in a sample enriched for T2DM. Specifically,the potential modifying effect of cigarette smoking was examined. A total of 28 SNPs in KALRN were genotyped in 1001 European Americans from 369 Diabetes Heart Study (DHS) families, as well as 762 population-based controls. The association between each SNP and both qualitative and quantitative CVD disease phenotypes was determined using generalized estimating equations and variance component models,respectively. Selected KALRN SNPs were found to be associated with both the qualitative (T2DM, CVD, metabolic syndrome)and quantitative traits (C-reactive protein and abdominal aortic calcified plaque). Interaction analysis and stratification were then used to test whether smoking modulates the genetic effects of KALRN. The strongest evidence of a modifying effect of smoking status was observed for rs9289231 and intima-media thickness (p=9.0x10^(-4)) and abdominal aortic calcified plaque (p=3.0x10^(-4)). Overall, following stratification by smoking status, the evidence of association with quantitative traits was more pronounced in smokers compared to non-smokers. The strongest association for smokers was between rs1720960 and abdominal aortic calcified plaque (p=2.6x10^(-5)), while in non-smokers there was no observed association. KALRN variants are associated with measures of CVD and T2DM in the DHS sample with smoking status observed to have a significant modifying effect on these associations.
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