Extreme genetic risk for type 1A diabetes in the post-genome era

Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO 80045-6511, USA.
Journal of Autoimmunity (Impact Factor: 8.41). 09/2008; 31(1):1-6. DOI: 10.1016/j.jaut.2008.03.003
Source: PubMed


A series of genes and loci influencing the genetic risk of type 1A (immune-mediated) diabetes are now well characterized. These include genes of the major histocompatibility complex (MHC), polymorphisms 5' of the insulin gene, and PTPN22, as well as more recently defined loci from genome-wide association studies. By far the major determinants of risk for type 1A diabetes are genes within or linked to the MHC and in particular alleles of class II genes (HLA-DR, DQ, and DP). There is evidence that MHC class I alleles contribute and there are additional MHC-linked influences such that for a major subset of relatives of patients there is a risk as high as 80% for siblings, and for the general population a risk as high as 20% can be defined at birth just by analyzing the MHC. We believe the search for additional MHC loci will require analysis of the remarkable long-range identity (up to 9 million base pairs) of extended MHC haplotypes. Current prediction algorithms will likely be greatly improved for the general population when the additional contributing loci of the MHC are defined.

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Available from: Erin E Baschal, Sep 17, 2014
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    • "Genome Wide Association Studies (GWAS) revealed over 20 genes that could be linked to disease susceptibility. Certain HLA haplotypes and mutations in the genes encoding insulin, PTPN22 (protein tyrosine phosphatase, non-receptor type 22, a molecule involved in the T cell receptor signaling pathway) and Interleukin-2 receptor are most prevalent in T1D affected individuals [1]. While knowledge of the genetic background of T1D has been multiplied in recent years, there is still no sweeping concept of the environmental factors that are involved in the development of the disease [2]. "
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    ABSTRACT: In type 1 diabetes, insulin producing pancreatic β-cells are attacked and destroyed by autoreactive T cells, which causes major impairments of blood glucose metabolism and finally development of life-threatening complications. Currently, the treatment of this devastating disease is based on the substitution of insulin and thus can be considered palliative. Curative treatment approaches by contrast need to target the underlying causes of disease development: in this case, the autoreactive immune system and the loss of active β-cell mass. In recent years, several clinical trials have been performed studying the effects of diverse immunomodulating agents in order to halt the autoreactive immune response or finding paths to repopulate β-cell mass that could restore euglycemia. While some of the treatments showed remarkable outcomes, most of the studies failed to improve the course of disease. The reason might be that none of the candidates currently under investigation are potent enough at tolerable dosages to hold the key for the cure. Subsequently, the idea of combining defined substances has evolved in order to detect synergistic effects and improve the strength of the therapeutic potential. Observations from mouse models and clinical experience from various other diseases where combination therapies often constitute the standard treatment strongly support this hypothesis. Here, we discuss promising monotherapeutic approaches, summarize current clinical trials and propose a rationale on how to prioritize different combinations of treatments.
    Preview · Article · Dec 2010 · International immunopharmacology
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    • "Genetic studies have contributed to portray the complexity of the disease and have established that multiple loci are carrying genes implicated in T1D in human [3] and animal models [4]. In human, more than 6 genes contribute to the disease [5,6] while over 20 loci have been described in the NOD mouse [7] but only few possible candidate genes have been unequivocally defined [8] other than the H2g7 Idd1 locus [7,9]. "
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    ABSTRACT: Autoimmune diabetes (T1D) onset is preceded by a long inflammatory process directed against the insulin-secreting beta cells of the pancreas. Deciphering the early autoimmune mechanisms represents a challenge due to the absence of clinical signs at early disease stages. The aim of this study was to identify genes implicated in the early steps of the autoimmune process, prior to inflammation, in T1D. We have previously established that insulin autoantibodies (E-IAA) predict early diabetes onset delineating an early phenotypic check point (window 1) in disease pathogenesis. We used this sub-phenotype and applied differential gene expression analysis in the pancreatic lymph nodes (PLN) of 5 weeks old Non Obese Diabetic (NOD) mice differing solely upon the presence or absence of E-IAA. Analysis of gene expression profiles has the potential to provide a global understanding of the disease and to generate novel hypothesis concerning the initiation of the autoimmune process. Animals have been screened weekly for the presence of E-IAA between 3 and 5 weeks of age. E-IAA positive or negative NOD mice at least twice were selected and RNAs isolated from the PLN were used for microarray analysis. Comparison of transcriptional profiles between positive and negative animals and functional annotations of the resulting differentially expressed genes, using software together with manual literature data mining, have been performed. The expression of 165 genes was modulated between E-IAA positive and negative PLN. In particular, genes coding for insulin and for proteins known to be implicated in tissue remodelling and Th1 immunity have been found to be highly differentially expressed. Forty one genes showed over 5 fold differences between the two sets of samples and 30 code for extracellular proteins. This class of proteins represents potential diagnostic markers and drug targets for T1D. Our data strongly suggest that the immune related mechanisms taking place at this early age in the PLN, correlate with homeostatic changes influencing tissue integrity of the adjacent pancreatic tissue. Functional analysis of the identified genes suggested that similar mechanisms might be operating during pre-inflammatory processes deployed in tissues i) hosting parasitic microorganisms and ii) experiencing unrestricted invasion by tumour cells.
    Full-text · Article · Oct 2009 · BMC Medical Genomics
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    • "The same seems to apply to the hypothesis of fetal microchimerism (FMC) originally developed on the basis of an increased allogenic cell traffic in females that could increase the risk for long-term microchimerism and therefore the development of autoimmunity. 2. MHC and non-MHC genetic influences in AID It has been well established that MHC alleles are associated with disease susceptibility for most AID [6] [7] [8] [9], and that such associations are proposed to play a critical role in the pathogenesis of autoimmunity . Although the underlying mechanisms of these associations are still obscure, it is currently believed that specific alleles of the Abbreviations: AID, autoimmune disease; FMC, fetal microchimerism; XCI, X chromosome inactivation; PID, primary immunodeficiency syndrome; AITD, autoimmune thyroid disease. "
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    ABSTRACT: It is known that autoimmune diseases cumulatively affect 5–10% of the general population.Although knowledge of pathogenesis has become more refined, laboratory diagnosis more accurate, and therapy more effective, the reasons for the female preponderance of these conditions remain unclear. The most intriguing theory to explain the female preponderance is currently related to sex chromosomes, as women with autoimmune diseases manifest a higher rate of circulating cells with a single X chromosome (i.e. X monosomy). In addition, there have been several reports on the role of X chromosome gene dosage through inactivation or duplication in autoimmunity. Taken together, sex chromosome changes might constitute the common trait of the susceptibility to autoimmune diseases.
    Preview · Article · Aug 2009 · Journal of Autoimmunity
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