Extreme genetic risk for type 1A diabetes

Barbara Davis Center for Childhood Diabetes and Human Medical Genetics Program, University Colorado Health Sciences Center, Aurora, CO 80045, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(38):14074-9. DOI: 10.1073/pnas.0606349103
Source: PubMed

ABSTRACT Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. The genotype associated with the highest risk for T1D is the DR3/4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3/4-DQ8 siblings of patients with T1D for identical-by-descent HLA haplotype sharing (the number of haplotypes inherited in common between siblings). The children were clinically followed with prospective measurement of anti-islet autoimmunity and for progression to T1D. Risk for islet autoimmunity dramatically increased in DR3/4-DQ8 siblings who shared both HLA haplotypes with their diabetic proband sibling (63% by age 7, and 85% by age 15) compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling (20% by age 15, P < 0.01). 55% sharing both HLA haplotypes developed diabetes by age 12 versus 5% sharing zero or one haplotype (P = 0.03). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DR3/4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3/4-DQ8 siblings sharing both HLA haplotypes with their proband is remarkable for a complex genetic disorder and provides evidence that T1D is inherited with HLA-DR/DQ alleles and additional MHC-linked genes both determining major risk. A subset of siblings at extremely high risk for T1D can now be identified at birth for trials to prevent islet autoimmunity.

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Available from: Sunanda Babu, Sep 26, 2015
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    • ". Pursuing the hypothesis that additional major determinants of Type 1 diabetes risk (in addition to DR/ DQ genes) are within or close to the MHC region, highly conserved HLA-F [24] [25] [26] [27] [28] [29] [30] [31] [32]. "
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    DESCRIPTION: This provides an up-to-date information about genetic of type 1 diabetes
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    • "The most obvious candidates for such intervention are mothers who had an affected child homozygous for disease-predisposing alleles at both HLA and INS loci. Such genotypes were associated with an extremely high disease risk for siblings (77). Apart from primary prevention of type 1 diabetes, future SSO-based therapeutics might be applicable to patients with significant residual β-cell activity at diagnosis and to those who are eligible to receive β-cell transplants and may benefit from increased intron-mediated enhancement of proinsulin expression from transplanted cells. "
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    ABSTRACT: Splice-switching oligonucleotides (SSOs) have been widely used to inhibit exon usage but antisense strategies that promote removal of entire introns to increase splicing-mediated gene expression have not been developed. Here we show reduction of INS intron 1 retention by SSOs that bind transcripts derived from a human haplotype expressing low levels of proinsulin. This haplotype is tagged by a polypyrimidine tract variant rs689 that decreases the efficiency of intron 1 splicing and increases the relative abundance of mRNAs with extended 5' untranslated region (5' UTR), which curtails translation. Co-expression of haplotype-specific reporter constructs with SSOs bound to splicing regulatory motifs and decoy splice sites in primary transcripts revealed a motif that significantly reduced intron 1-containing mRNAs. Using an antisense microwalk at a single nucleotide resolution, the optimal target was mapped to a splicing silencer containing two pseudoacceptor sites sandwiched between predicted RNA guanine (G) quadruplex structures. Circular dichroism spectroscopy and nuclear magnetic resonance of synthetic G-rich oligoribonucleotide tracts derived from this region showed formation of a stable parallel 2-quartet G-quadruplex on the 3' side of the antisense retention target and an equilibrium between quadruplexes and stable hairpin-loop structures bound by optimal SSOs. This region interacts with heterogeneous nuclear ribonucleoproteins F and H that may interfere with conformational transitions involving the antisense target. The SSO-assisted promotion of weak intron removal from the 5' UTR through competing noncanonical and canonical RNA structures may facilitate development of novel strategies to enhance gene expression.
    Nucleic Acids Research 06/2014; 42(12). DOI:10.1093/nar/gku507 · 9.11 Impact Factor
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    • "However, HLA genotyping in firstdegree relatives of T1D probands can be useful. Aly et al. (2006) reported that risk for islet autoimmunity drastically increased in DR3/4- DQ2/DQ8 siblings who shared both HLA haplotypes identical by descent with their diabetic proband sibling (63% by age 7, and 85% by age 15) as compared with siblings who did not share both HLA haplotypes with their diabetic proband siblings (Fig. 3). These data indicate that HLA genotyping at birth may identify individuals at very high risk of developing T1D, before the occurrence of clear signs of humoral autoimmunity and eventually overt disease. "
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    ABSTRACT: Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic β cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated β-cell injury and, in turn, preserving β-cell function in type 1 diabetes mellitus.
    Cold Spring Harbor Perspectives in Medicine 10/2012; 2(10). DOI:10.1101/cshperspect.a012831 · 9.47 Impact Factor
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