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      Association of Genetic polymorphism of PPARγ-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus

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          Abstract

          Type 2 diabetes mellitus (T2DM) is a non-autoimmune, complex, heterogeneous and polygenic metabolic disease condition characterized by persistent elevated blood glucose levels (hyperglycemia). India as said to be the diabetic capital of the world is likely to experience the largest increase in T2DM and a greater number of diabetic individuals in the world by the year 2030. Identification of specific genetic variations in a particular ethnic group has a critical role in understanding the risk of developing T2DM in a much efficient way in future. These genetic variations include numerous types of polymorphisms among which single nucleotide polymorphisms (SNPs) is the most frequent. SNPs are basically located within the regulatory elements of several gene sequences. There are scores of genes interacting with various environmental factors affecting various pathways and sometimes even the whole signalling network that cause diseases like T2DM. This review discusses the biomarkers for early risk prediction of T2DM. Such predictions could be used in order to understand the pathogenesis of T2DM and to better diagnostics, treatment, and eventually prevention.

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          The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

          Thomas Gerken, Christophe A J Girard, Yi-Chun Tung … (2007)
          Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
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            PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.

            B Spiegelman (1998)
            The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance.
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              The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.

              D. Altshuler, J. Hirschhorn, M Klannemark … (2000)
              Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.
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                Author and article information

                Contributors
                Shania Abbas
                Syed Tasleem Raza
                Faisal Ahmed
                Absar Ahmad
                Saliha Rizvi
                Farzana Mahdi
                Journal
                Journal ID (nlm-ta): J Biomed Sci
                Journal ID (iso-abbrev): J. Biomed. Sci
                Title: Journal of Biomedical Science
                Publisher: BioMed Central
                ISSN (Print): 1021-7770
                ISSN (Electronic): 1423-0127
                Publication date Collection: 2013
                Publication date (Electronic): 25 October 2013
                Volume: 20
                Issue: 1
                Page: 80
                Affiliations
                [1 ]Molecular Biology Lab, Department of Biochemistry, Era’s Lucknow Medical College and Hospital, Lucknow 226003, India
                Article
                Publisher ID: 1423-0127-20-80
                DOI: 10.1186/1423-0127-20-80
                PMC ID: 4015124
                PubMed ID: 24156506
                SO-VID: e855e08d-4ff6-44b0-b79a-9b5984124996
                Copyright © Copyright © 2013 Abbas et al.; licensee BioMed Central Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 6 July 2013
                Date accepted : 1 October 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: genome sequencing,single nucleotide polymorphism,genetic polymorphism,peroxisome proliferator-activated receptor gamma,angiotensin converting enzyme,methylene tetrahydrofolate reductase,fatty acid binding protein-2,fat mass and obesity associated gene,type 2 diabetes mellitus
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: genome sequencing, single nucleotide polymorphism, genetic polymorphism, peroxisome proliferator-activated receptor gamma, angiotensin converting enzyme, methylene tetrahydrofolate reductase, fatty acid binding protein-2, fat mass and obesity associated gene, type 2 diabetes mellitus

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