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- Gu, Tianwei, et al.
(författare)
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IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy
- 2012
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Ingår i: Journal of diabetes and its complications. - : Elsevier BV. - 1056-8727 .- 1873-460X. ; 26:5, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (120) and diabetic nephropathy (ON). Its protein functionally binds to 5'-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN. Materials and Methods: Three cohorts including T1D with and without DN (n = 1139) of European descents from the GoKinD study, Swedish T1D with and without ON (n = 303) and Czech control subjects without diabetes, T1D, T2D with and without ON (n = 1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot. Results: An association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P = 0.037, OR = 0.69 95% CI 0.49-0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and ON in male patients with T1D was still significant (P = 0.030, OR = 0.73, 95% CI 0.54-0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P = 0.038, OR = 0.67 95% CI 0.46-0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P = 0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5 weeks but not at 26 weeks. Conclusions: The present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D. (C) 2012 Elsevier Inc. All rights reserved.
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| 2. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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| 3. |
- Gu, Tianwei
(författare)
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Genetic and epigenetic studies of diabetes and diabetic nephropathy with focus on the IGF-IGFBP axis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes and diabetic nephropathy (DN) are complex diseases reflecting a complex interplay between genetic and non-genetic factors. The insulin-like growth factor (IGF) - IGF binding protein (IGFBP) axis plays an important role in the development of diabetes and DN. Recent reports have demonstrated that genetic polymorphisms in this axis are associated with diabetes and DN. However, the information of epigenetic study is very limited. In this study, we selected four genes from this axis including IGF1, IGF2, IGFBP1 and IGF2BP2 to evaluate their genetic and epigenetic associations with diabetes and DN. In parallel, we analyzed the serum protein levels. SNP rs35767 in the IGF1 gene promoter region has been reported to be associated with insulin resistance and circulating IGF-I levels. In Study I, we analyzed IGF1 DNA methylation levels at CpG sites in the promoter region including this SNP and measured serum IGF-I concentration in Swedish subjects with normal glucose tolerance (NGT) or type 2 diabetes (T2D). Data suggested that increased DNA methylation in the gene promoter and decreased circulating IGF-I levels are associated with T2D. IGFBP-1 is produced in liver and mainly regulated by insulin. Clinical observations have demonstrated that high levels of circulating IGFBP-1 are associated with T1D, while low serum levels are associated with the risk of T2D. There is a CpG island at the promoter and 5’-untranlated region (5’-UTR) of the IGFBP1 gene. We analyzed IGFBP1 DNA methylation levels in Swedish T2D patients (Study II) and T1D patients with or without DN (Study III). Results demonstrated that IGFBP1 DNA methylation levels were decreased in T1D patients but increased in T2D patients in comparison with NGT subjects. Furthermore, decreased and increased IGFBP-1 serum levels were respectively associated with T2D and T1D. The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to diabetes and DN. The protein encoded IGF2BP2 binds to 5'-UTR of the imprinting IGF2 gene, which is located on chromosome 11p15.5. In Study IV, we genotyped SNPs rs10770125 (A/G) and rs4402960 (G/T) in the IGF2 and IGF2BP2 genes respectively. Diabetes patients with or without DN and NGT subjects from GoKinD, Czech and Swedish populations were enrolled in this study. Data showed that the IGF2BP2 polymorphism rs4402960 was associated with T2D. This IGF2BP2 polymorphism and rs10770125 in the IGF2 gene were found to be associated with DN in male T1D patients. In conclusion, our studies provide evidence that the IGF1, IGF2, IGFBP1 and IGF2BP2 genes have genetic and epigenetic effects in diabetes and DN. To better understand the importance of our findings, further investigations of tissue specific DNA methylation levels and their impacts on translated proteins are needed.
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| 4. |
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| 5. |
- Tan, Tianwei, et al.
(författare)
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Cross-linked agarose for separation of low molecular weight natural products in hydrophilic interaction liquid chromatography
- 2010
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Ingår i: Biotechnology Journal. - : Wiley. - 1860-6768. ; 5:5, s. 505-510
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Forskningsöversikt (refereegranskat)abstract
- Following its market introduction in 1982, the cross-linked 12% agarose gel media Superose 12 has become widely known as a tool for size exclusion chromatography of proteins and other biological macromolecules. In this review it is shown that, when appropriate mobile phases are used, Superose possesses adsorption properties similar to that of traditional media for hydrophilic interaction liquid chromatography (HILIC). This is illustrated by the separation and purification of low molecular weight compounds such as polyphenols including active components of traditional Chinese medicinal herbs and green tea. Structural features of the cross-linked agarose that likely cause the observed adsorption effects are discussed aswell. These are identified as being primarily ether bonds acting as strong hydrogen bond acceptors as well as hydrophobic residues originating from the cross-linking reagents.
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