Mechanisms of genetic susceptibility to type I diabetes: beyond HLA

Anjos, Suzana M.; Polychronakos, Constantin

doi:10.1016/j.ymgme.2003.11.010

Cited by 81 publications

(57 citation statements)

References 80 publications

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“…Other studies have reported a functional role for the CTLA4 þ 49 variant, in which the þ 49G (Ala19) allele is associated with incomplete glycosylation of the signal peptide, altered processing in the endoplasmic reticulum, and lower cell surface levels in transfected cells and also for the -318 promoter variant. 17 Interestingly, the NOD mouse, known to be predisposed to autoimmune disease, also has a defect in expression of a CTLA4 isoform, 7 and Table 2 Healthy control (a) allele frequencies and counts of CTLA4 SNPs and (b) haplotype frequencies of CTLA4 SNPs recent data have suggested that the HLA-DQ8 transgenic mouse develops a coeliac disease/dermatitis herpetiformis like phenotype on the NOD background. 18 Our data suggest that coeliac disease is most strongly associated with a haplotype of the CTLA4 gene, rather than any of the individual variants analysed.…”

Section: Discussionmentioning

confidence: 99%

A common CTLA4 haplotype associated with coeliac disease

et al. 2005

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Coeliac disease is a common enteropathy with a strong inherited risk characterised by dietary wheat, rye and barley induced T-cell activation. Although there is replicated linkage to 2q33, results are inconsistent from association studies of the most promising candidate genes: the CD28/CTLA4/ICOS cluster. CTLA4 plays a key role in regulating T lymphocyte mediated inflammatory responses, and variants in the 3 0 region influence development of diabetes and thyroid disease. We genotyped CTLA4 variants (À1722 C/T, À658 T/C, À318 C/T, þ 49 A/G, þ 1822 C/T, CT60 A/G) to tag all common haplotypes (45% frequency) and an ICOS variant (IVS þ 173 C/T) in 340 white UK Caucasian coeliac disease cases. Strict ascertainment criteria for coeliac cases required both villous atrophy at diagnosis and positive serology. In total, 973 healthy controls were available for SNP, and 705 for CTLA4 haplotype, based association analyses. Coeliac disease showed weak association with the CTLA4 þ 1822T (P ¼ 0.019) and CT60 G (P ¼ 0.047) alleles. Strong association was seen with a common CTLA4 haplotype (P ¼ 0.00067, odds ratio 1.41) of frequency 32.7% in coeliac disease and 25.5% in healthy controls. A common CTLA4 haplotype shows strong association with coeliac disease, and contains multiple alleles reported to affect immunological function. Loss of tolerance to dietary antigens in coeliac disease may be mediated in part by heritable variants in co-signalling genes regulating T-cell responses.

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Section: Discussionmentioning

confidence: 99%

A common CTLA4 haplotype associated with coeliac disease

et al. 2005

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“…10 Identification of the diseasecausing polymorphism or haplotype has proven to be far more challenging, due to the extent of LD in the region. To this end, detailed functional analysis is required.…”

Section: Discussionmentioning

confidence: 99%

Allelic effects on gene regulation at the autoimmunity-predisposing CTLA4 locus: a re-evaluation of the 3′ +6230G>A polymorphism

et al. 2005

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Genetic variation at a linkage disequilibrium block encompassing the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene influences susceptibility to autoimmunity, but identifying the polymorphism(s) responsible for this effect has been challenging. Recently, a single-nucleotide polymorphism (SNP) located 3 0 to the known polyadenylation site of CTLA4 ( þ 6230G4A) and strongly associated with autoimmune disease was reported to regulate levels of soluble CTLA4 isoform (sCTLA4) but not the full-length isoform. The purpose of the present study is to define the mechanistic effect of the 3 0 SNP on the isoforms of CTLA4 (alternative splicing vs polyadenylation vs effects on RNA stability). However, using allele-specific single-nucleotide primer extension, we found no difference between mRNA transcripts derived from either þ 6230G4A allele in 11 heterozygous individuals, in either of the two known CTLA4 isoforms. We also found no effect of this polymorphism on ICOS (inducible costimulator), a putative downstream target. In addition, repeated attempts at 3 0 RACE (3 0 rapid amplification of cDNA ends) were unsuccessful in amplifying any contiguous sequence past the known CTLA4 polyadenylation site and no such sequence was found in the EST databases. We conclude that the mechanism of the observed association of the þ 6230 SNP with autoimmune disease remains to be determined, but does not involve modulation of steady-state mRNA of any known CTLA4 isoform.

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“…The thymus deletes autoreactive T cells in a dosedependent manner (Anjos and Polychronakos 2004). Therefore, expression levels of proteins in the thymus can also influence whether a T cell is clonally deleted or allowed to mature.…”

Section: Antigen Recognitionmentioning

confidence: 99%

“…Heterozygous knockout mice (Ins2 þ /2 ) show accelerated disease over normal wild type NOD mice but less than homozygous knockout mice (Thebault-Baumont et al 2003, Anjos and Polychronakos, 2004. In contrast, Ins1 knockout mice (Ins1 2 /2 ) are protected from diabetes but not from sialitis or development of insulin autoantibodies .…”

Section: Preproinsulin Proinsulin and Insulinmentioning

confidence: 99%

Insulin as a Primary Autoantigen for Type 1A Diabetes

Jasinski¹,

Eisenbarth

2005

Journal of Immunology Research

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Type 1A diabetes mellitus is caused by specific and progressive autoimmune destruction of the beta cells in the islets of Langerhans whereas the other cell types in the islet (alpha, delta, and PP) are spared. The autoantigens of Type 1A diabetes may be divided into subgroups based on their tissue distributions: Beta-cell-specific antigens like insulin, insulin derivatives, and IGRP (Islet-specific Glucose-6-phosphatase catalytic subunit Related Peptide); neurendocrine antigens such as carboxypeptidase H, insulinoma-associated antigen (IA-2), glutamic acid decarboxylase (GAD65), and carboxypeptidase E; and those expressed ubiquitously like heat shock protein 60 (a putative autoantigen for type 1 diabetes). This review will focus specifically on insulin as a primary autoantigen, an essential target for disease, in type 1A diabetes mellitus. In particular, immunization with insulin peptide B:9-23 can be used to induce insulin autoantibodies and diabetes in animal models or used to prevent diabetes. Genetic manipulation of the insulin 1 and 2 genes reciprocally alters development of diabetes in the NOD mouse, and insulin gene polymorphisms are important determinants of childhood diabetes. We are pursuing the hypothesis that insulin is a primary autoantigen for type 1 diabetes, and thus the pathogenesis of the disease relates to specific recognition of one or more peptides.

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Mechanisms of genetic susceptibility to type I diabetes: beyond HLA

Cited by 81 publications

References 80 publications

A common CTLA4 haplotype associated with coeliac disease

A common CTLA4 haplotype associated with coeliac disease

Allelic effects on gene regulation at the autoimmunity-predisposing CTLA4 locus: a re-evaluation of the 3′ +6230G>A polymorphism

Insulin as a Primary Autoantigen for Type 1A Diabetes

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