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Title: Molecular SNPlotypes™ with common alleles reflects expression profile in Diabetes Mellitus Type 2
Authors: Al-Ashtar, Ali Ahmed
Keywords: Diabetes
Metabolic syndrome
Idiosyncratic drug reactions
Genetic disorders
Issue Date: 2008
Citation: Al-Ashtar, A.A. (2008). Molecular SNPlotypes™ with common alleles reflects expression profile in Diabetes Mellitus Type 2 (Doctoral dissertation).
Abstract: Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder and is one of the cardiovascular risk factors cumulatively giving rise to a metabolic syndrome (MS). The pathophysiology of T2DM is related to underplaying multiple genes. In this study 20 Single Nucleotide Polymorphisms (SNPs) panel I, associated with T2DM were characterised after PCR and RFLP using DNA samples from Maltese and Libyan T2DM patients, and their respective reference populations. 7/20 cognate SNPs (panel II) at different loci representing different genes (ADRAB~2 [nt46 A-7G], FABP2 [codon 54 G-7A], UCPl [nt3826 A-7G], LEPTIN [nt -2549 C-7A], IPFl [codon 18 T-7C], IL-6 [-174 G-7C], TCF7L2 [IVS3 T-7G]) showed significance association with T2DM having a significant odds ratio of 1.7 to 4.2. These genes represent inflammatory response genes, metabolic syndrome genes and MODY genes. An innovative concept of SNPlotyping TM has revealed the impact of the number of mutant alleles resulting in a SNPlotypingTM score that enhances the association with T2DM patients in the 2 populations. The distribution of SNPs in the different SNPlotypesTM indicates that ~2 adrenergic receptor is highly represented (44%) followed by FABP2 (44%), TCF7L2 (41 %), Leptin (35%), IL6 (27%) and UCPl (24%). The SNPlotype with the highest association in the population study was found to be significant and inherited together with the disorder in a family study. Another part of this study the response to drugs (Insulin, Metformin and Glibenclamide) by the selected Maltese T2DM patients representing the different SNPlotypes was measured as a function of differential expression of a gene using RT-PCR on mRNA extracted from monocyte of Maltese T2DM patients. Only ~2 adrenergic receptor (ADRAB~2) transcripts were detected in the untreated and treated monocytes. The differential expression of ADRAB~2 indicates that there is a relation between the response to the drug and the SNPlotype of the patient. Interestingly, the expression of ADRAB~2 was downregulated in response to Insulin and Metformin in patients with SNPlotypes lacking the ADRAB~2 mutation, while the expression was upregulated in the other SNPlotypes. The outcome of ADRAB~2 mRNA transcript was dependent on patient SNPlotypeTM, when ranked by wildtype and mutant UCPl and ADRAB~2 polymorphisms. In conclusion some metabolic and inflammatory alleles where characterized in the Maltese and Libyan populations. SNPlotypeTM enhances the association to measure the risk for a particular disorder and we give evidence that it can be used to classify patients into potentially therapeutic groups.
Description: PH.D.
Appears in Collections:Dissertations - FacM&S - 2008
Dissertations - FacM&SPB - 2008

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