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      Genetic variants of nuclear factor erythroid‐derived 2‐like 2 associated with the complications in Han descents with type 2 diabetes mellitus of Northeast China

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          Abstract

          The transcription factor nuclear factor erythroid 2‐like 2 ( NFE2L2) is essential for preventing type 2 diabetes mellitus (T2 DM)‐induced complications in animal models. This case and control study assessed genetic variants of NFE2L2 for associations with T2 DM and its complications in Han Chinese volunteers. T2 DM patients with ( n = 214) or without ( n = 236) complications, or healthy controls ( n = 359), were genotyped for six NFE2L2 single nucleotide polymorphisms ( SNPs: rs2364723, rs13001694, rs10497511, rs1806649, rs1962142 and rs6726395) with TaqMan Pre‐Designed SNP Genotyping and Sequence System. Serum levels of heme oxygenase‐1 ( HMOX1) were determined through enzyme‐linked immunosorbent assay. Informative data were obtained for 341 cases and 266 controls. Between T2 DM patients and controls, the genotypic and allelic frequencies and haplotypes of the SNPs were similar. However, there was a significant difference in genotypic and allelic frequencies of rs2364723, rs10497511, rs1962142 and rs6726395 between T2 DM patients with and without complications, including peripheral neuropathy, nephropathy, retinopathy, foot ulcers and microangiopathy. Furthermore, HMOX1 levels were significantly higher in T2 DM patients with complications than in controls. Multiple logistic regression analysis, however, showed that only rs2364723 significantly reduced levels of serum HMOX1 in T2 DM patients for the GG genotype carriers compared with participants with CG+ CC genotype. The data suggest that although NFE2L2 rs2364723, rs10497511, rs1962142 and rs6726395 were not associated with T2 DM risk, they were significantly associated with complications of T2 DM. In addition, only for rs2364723 higher serum HMOX1 levels were found in the T2 DM patients with CG+ CC than those with GG genotype.

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          Most cited references28

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          Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.

          Hypersensitive site 2 located in the beta-globin locus control region confers high levels of expression to the genes of the beta-globin cluster. A tandem repeat of the consensus sequence for the transcription factors AP1 and NF-E2 (activating protein 1 and nuclear factor erythroid 2, respectively) is present within hypersensitive site 2 and is absolutely required for strong enhancer activity. This sequence binds, in vitro and in vivo, to ubiquitous proteins of the AP1 family and to the recently cloned erythroid-specific transcription factor NF-E2. Using the tandem repeat as a recognition site probe to screen a lambda gt11 cDNA expression library from K562 cells, we isolated several DNA binding proteins. Here, we report the characterization of one of the clones isolated. The gene, which we named Nrf2 (NF-E2-related factor 2), is encoded within a 2.2-kb transcript and predicts a 66-kDa protein with a basic leucine zipper DNA binding domain highly homologous to that of NF-E2. Although Nrf2 is expressed ubiquitously, a role of this protein in mediating enhancer activity of hypersensitive site 2 in erythroid cells cannot be excluded. In this respect, Nrf2 contains a powerful acidic activation domain that may participate in the transcriptional stimulation of beta-globin genes.
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            Genetic variants and the risk of gestational diabetes mellitus: a systematic review.

            Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies. Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNP-GDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity. Overall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (-30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95% CIs) of 1.44 (1.29-1.60, P < 0.001) per T allele of rs7903146 and 1.46 (1.15-1.84, P = 0.002) per T allele of rs12255372. In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion.
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              Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression.

              The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-α expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-κΒ. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2(-/-) mice. Nfe2l2(-/-) mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2(-/-) mice in sepsis also generated higher hepatic TNF-α mRNA levels, lower NRF-1 and PGC-1α mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-x(L) gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis.
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                Author and article information

                Contributors
                miaolining55@163.com
                L0cai001@louisville.edu
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                04 July 2016
                November 2016
                : 20
                : 11 ( doiID: 10.1111/jcmm.2016.20.issue-11 )
                : 2078-2088
                Affiliations
                [ 1 ] Department of Gynecology and ObstetricsSecond Hospital of Jilin University ChangchunChina
                [ 2 ] Department of NephropathySecond Hospital of Jilin University ChangchunChina
                [ 3 ] Kosair Children's Hospital Research Institute Department of PediatricsUniversity of Louisville Louisville KYUSA
                [ 4 ] Division of Endocrinology Department of PediatricsUniversity of Louisville Louisville KYUSA
                [ 5 ] Wendy L. Novak Diabetes Care Center Kosair Children's HospitalUniversity of Louisville Louisville KYUSA
                Author notes
                [*] [* ] Correspondence to: Prof. Lining MIAO

                E‐mail: miaolining55@ 123456163.com

                Dr. Lu CAI

                E‐mail: L0cai001@ 123456louisville.edu

                Article
                JCMM12900
                10.1111/jcmm.12900
                5082403
                27374075
                5c3074cf-54a7-45c5-a7ad-b6deae1ba82d
                © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 November 2015
                : 10 May 2016
                Page count
                Figures: 0, Tables: 7, Pages: 11, Words: 7608
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81170669
                Funded by: National Key Technology R&D Program
                Award ID: 2011BAI10B00
                Funded by: Postgraduate Innovation Centre of Jilin University
                Award ID: 20121122
                Funded by: American Diabetes Association
                Award ID: 1‐15‐BS‐018
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm12900
                November 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.6 mode:remove_FC converted:26.10.2016

                Molecular medicine
                nfe2l2 gene mutation,diabetes,diabetic complications,chinese population,nrf2 polymorphism

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