Genetic Susceptibility to Type 1 Diabetes in the Intracellular Pathway of Antigen Processing – A Subject Review and Cross-Study Comparison

Sia, Charles; Weinem, Michael

doi:10.1900/rds.2005.2.40

Cited by 14 publications

(11 citation statements)

References 97 publications

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“…However, several other studies did not find LMP2 R/H polymorphism to be associated with T1D [27,30]. A meta analysis done to resolve this problem of variable results suggested that LMP2 RH genotype seemed to be associated with T1D [31], the results opposite to ours where we observed RR genotype to be disease conferring and heterozygous RH to be reduced in the patients compared to controls. These differences could be due to different ethnicity of the individuals studied in the present report.…”

Section: Discussioncontrasting

confidence: 99%

Haplotypes of Polymorphic Antigen Processing Genes for Low Molecular Mass Polypeptides (LMP2 and LMP7) are Strongly Associated with Type 1 Diabetes in North India

Saida¹,

Dani²,

Patnaik³

et al. 2014

J Diabetes Metab

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Section: Discussioncontrasting

confidence: 99%

Haplotypes of Polymorphic Antigen Processing Genes for Low Molecular Mass Polypeptides (LMP2 and LMP7) are Strongly Associated with Type 1 Diabetes in North India

Saida¹,

Dani²,

Patnaik³

et al. 2014

J Diabetes Metab

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“…In contrast, a series of other genes, such as the coding sequences for TAP (transporters associated with antigen processing), LMP (large multifunc- Copyright © by the SBDR tional proteases) and TNF-α, the MIC-A (MHC class I chain-related A) gene, as well as identified (the insulin gene on chromosome 11p15) and largely unidentified genes on other chromosomes (e.g. 6q and 11q) have been linked to the disease corroborating its polygenic nature [1][2][3][4][5]. This has invoked an additive model, from which it was possible to predict that a maximum of only 0.15% of the general population is at 100% risk of T1DM, about 5% is at intermediate risk, while the remaining population has a risk of almost 0 [6].…”

Section: ■ Abstractmentioning

confidence: 99%

The Role of HLA Class I Gene Variation in Autoimmune Diabetes

Sia¹,

Weinem²

2005

Rev Diab Stud

Self Cite

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■ AbstractThe use of DNA-based genetic typing has enabled the identification of type 1 diabetes mellitus (T1DM) susceptible and protective major histocompatibility complex (MHC) class II alleles and haplotypes. The application of this approach has also progressed to locate MHC class I alleles that contribute to the clinicopathology of T1DM. Recent studies have shown a widespread involvement of genes from the MHC class I gene region in the clinicopathology of T1DM. These genes are demonstrated to be involved in contributing to progression from the preclinical stage of the disease, which is characterized by the occurrence of islet-specific antibodies, to clinical disease and also to the occurrence of autoimmunity. They can either contribute directly to disease development or indirectly in concert with other susceptible MHC class II alleles or haplotypes via linkage disequilibrium. Class I alleles may also be negatively associated with T1DM. These findings are useful for the development of future strategies in designing tolerogenic approaches for the prevention or even reversal of T1DM. In this article, the latest evidence for the different kinds of participation of HLA class I genes in the etiology of T1DM is reviewed. A metaanalysis which included existing association studies was also carried out in order to re-assess the relevance of class I genes in diabetes development. The analysis of an enlarged heterogeneous sample confirmed the involvement of previously detected serotypes in the etiology of T1DM, such as A24, B8 and B18, and revealed hitherto unknown associations with B60 and B62. The analysis points out that much of the conflicting results of previous association studies originate from inadequate sample sizes and accentuate the value of future investigations of larger samples for identifying linkage in multigenic diseases.Keywords: type 1 diabetes · HLA class I · cross-study analysis · serotype association Introduction ype 1 diabetes mellitus (T1DM) is a multifactorial and multigenic autoimmune organ disease characterized by progressive T cell-mediated destruction of the pancreatic β-cells . The major determinants of this disease are genes of the human leucocyte antigen (HLA) region, which are highly polymorphic. In a multiplicative model, they account for between 20 and 53% of T1DM susceptibility markers [1]. Gene products of HLA class I genes function as antigen presenting molecules for CD8 + cytotoxic T lymphocytes (CTL) and determine the antigen specificity of the CTL-mediated immune response against pathogens and self-antigens. T cell reactions with islet-specific self-antigens may lead to clonal proliferation of autoreactive CTLs directed against pancreatic β-cells provoking destruction of these organ cells.Initial genetic analyses clearly rejected a dominant major locus. In contrast, a series of other genes, such as the coding sequences for TAP (transporters associated with antigen processing), LMP (large multifunc- Copyright © by the SBDR tional proteases) and TNF-α, the MIC-A (MHC class I chain-r...

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“…During therapy, some beta-cells of the endocrine pancreas exhibit cross-resistance to a broad range of these structurally unrelated drugs known as 'multidrug resistance'. Multidrug resistance in cultured primary insulinoma cell lines has been associated with the increased expression of several energy dependent transporter proteins including Pglycoprotein (ABCB1), MRP1 (ABCC1) and BCRP (ABCG2) [2].…”

Section: Mrp1/abcc1 Transportersmentioning

confidence: 99%

“…Different allelic variants (TAP1A-E and TAP2A-H) have been identified but due to their close proximity to the HLA DQB1-DQA1-DRB1 loci it has been difficult to asses specific risk alleles in TAP and many controversial studies exist. A cross-study review [2] has demonstrated recently that non-synonymous polymorphisms at codons 333 of TAP1, and codons 687 and 651 in TAP2 are associated with T1D risk. The genotypes TAP1*333-A/F, TAP2*687-A/A and TAP2*651-A/F are positively related to disease, while the genotypes TAP1*333-A/A, TAP2*687-A/B and TAP2*651-A/A reduce the risk of developing T1D.…”

Section: Mutations In Tap2 Associated With Diabetes Typementioning

confidence: 99%

Multiple Drug Resistance Associated with Function of ABC-Transporters in Diabetes Mellitus: Molecular Mechanism and Clinical Relevance

Koehn

Fountoulakis²,

Krapfenbauer

2008

IDDT

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ATP-binding cassette (ABC) transporters are involved in a variety of physiological processes such as lipid metabolism, ion homeostasis and immune functions. A large number of these proteins have been causatively linked to rare and common human genetic diseases including familial high-density lipoprotein deficiency, retinopathies, cystic fibrosis, diabetes and cardiomyopathies. Furthermore, genetic variations in ABC transporter genes and deregulated expression patterns significantly contribute to drug resistance in human cancer and pancreatic beta cells and alter the pharmacokinetic properties of a variety of drugs. Up-to-date 15 ABC transporters have been identified in human pancreatic beta cells, however only a few of them are identified to date as proteins/genes associated with multidrug resistance (MDR) in diabetes mellitus. Prominent members include the multidrug resistance protein 1 (MRP1/ABCC1), sulfonylurea receptor 1 (SUR1/ABCC8), the multi drug transporter TAP2 and member of the ATP-binding cassette transporter subfamily A (ABCA1). ABCC8 is a subunit of the pancreatic beta-cell K(ATP) channel and plays a key role in the regulation of glucose-induced insulin secretion. Although the physiological role of these transporters to MDR is not yet fully understood, they play an important role in the blood-membrane barrier in pancreatic beta cells. The aim of this article is to provide an overview and to present few examples of drug treatment in MDR in diabetes mellitus associated with function of ABC-transporters.

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Genetic Susceptibility to Type 1 Diabetes in the Intracellular Pathway of Antigen Processing – A Subject Review and Cross-Study Comparison

Cited by 14 publications

References 97 publications

Haplotypes of Polymorphic Antigen Processing Genes for Low Molecular Mass Polypeptides (LMP2 and LMP7) are Strongly Associated with Type 1 Diabetes in North India

Haplotypes of Polymorphic Antigen Processing Genes for Low Molecular Mass Polypeptides (LMP2 and LMP7) are Strongly Associated with Type 1 Diabetes in North India

The Role of HLA Class I Gene Variation in Autoimmune Diabetes

Multiple Drug Resistance Associated with Function of ABC-Transporters in Diabetes Mellitus: Molecular Mechanism and Clinical Relevance

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