The official version of the rule will be published in the Federal Register. This final rule addresses various requirements applicable to health insurance issuers, Affordable Insurance Exchanges ExchangesNavigators, non-navigator assistance personnel, and other entities under the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of collectively referred to as the Affordable Care Act. Specifically, the rule establishes standards related to product discontinuation and renewal, quality reporting, non-discrimination standards, minimum certification standards and responsibilities of qualified health plan QHP issuers, the Small Business Health Options Program, and enforcement remedies in Federally-facilitated Exchanges.
The invention also relates to the identification of genetic variation in ZnT8 that is described herein as an important player in the initiation of the disease process and the progression of autoimmunity to clinical diabetes.
These findings have allowed the inventors to provide new diagnostic tools that can be used to refine the prognostic evaluation of the course of the disease and to monitor the effectiveness of therapeutic interventions in the preclinical phase of the disease.
The molecule itself, derived peptides, peptide analogs and secondary immune reagents also serve as the basis of therapeutic interventions to prevent the onset or progression of autoimmunity to clinical disease. The ability to determine the genotype of an individual as soon as one is born provides a distinct advantage to implementing therapeutic measures, since prevention of the emergence is likely to be easier than reversal of the autoimmune process once it is established.
Previously, as discussed above, insulin was defined as a candidate gene based on its tissue association, GAD65 and IA-2 from the ability of patient sera to immunoprecipitate proteins from radiolabelled isletsand IGRP as a peptide bound to MHC H-2 Kd that stimulated a T-cell clone derived from a spontaneously diabetic mouse.
The inventors have asked the question of whether one can develop a more systematic approach to the identification of target autoantigens based upon what is now understood of the cellular and molecular biology of autoantigens, and the availability of tools to study and analyze genome-wide expression in different tissue by microarray analysis.
Robust assays can then be used to detect cellular and humoral immune responses to such molecules.
The results of this research are described below, with particular emphasis on the discovery of a novel target autoantigen, namely ZnT8. More specifically, the structural biology of antigen presentation and T-cell recognition provided relatively few clues to identification of novel T1D autoantigens, since both MHC and T-cell receptor molecules have broad ranges of peptide binding specificities and relatively low affinities.
It has proven difficult to identify native epitopes even when detailed knowledge of the binding properties of mimotope peptides is known, simply because the number of contact residues is small and conservative amino acid substitutions are readily accepted.
The present inventors describe herein the development of a knowledge-based algorithm to identify candidate autoantigens on a genome wide basis. A meta-analysis based on gene ontology functions and information such as gene location is then considered before embarking on an evaluation of a shortlist of candidates based upon spontaneous and primed cell-mediated autoimmune responses in NOD mice and humoral autoreactivity determined in both NOD mice and human sera.
The microarray data that underpins this approach has largely been obtained.
Using this approach, the present inventors have identified Zinc transporter protein 8 ZnT8, also known as Slc30A8 as a new autoantigen target for prognostic, diagnostic and therapeutic methods associated with T1D.
The present inventors have demonstrated that ZnT8 is a target for autoantibodies in human subjects that develop T1D, and have identified polymorphic variants of ZnT8 as genetic markers of type 1 diabetes susceptibility, autoimmune status, autoantibody specificity and disease progression and severity.
Autoantibodies to ZnT8 appear before the development of clinical disease and are believed to be a novel marker for incipient diabetes. In addition, the inventors have discovered that the ZnT8 autoantibodies target two different regions of the molecule, and that one of these regions incorporates one of 3 different amino acids that play a crucial role in determining both the specificity and the magnitude of the immune response.
Determination of the genotype of an individual using a single nucleotide polymorphism analysis at any time prior to the development of autoimmunity and diabetes provides information regarding which variant amino acid is encoded, and can therefore be used in making clinical decision regarding treatment and care.
In addition, the present invention permits the precise analysis of the specificity of the autoantibodies that are directed at ZnT8, and further classification of the antibodies with respect to which of the variant forms of ZnT8 are targeted by the immune system.
The response of the individual can be categorized as being one of 8 different responses: Such stratification of the autoantibody response is proposed herein to provide information about the disease progression and will be essential in determining how to treat T1Dautoimmunity with antigen-specific therapeutic agents.
More specifically, the inventors have shown that: Older children show a genotype frequency similar to that reported in the normal population.
Accordingly, the CC genotype may be considered to be a risk factor for diabetes. Prior to the present invention, a partial nucleotide sequence encoding a portion of ZnT8 was identified and reported in a publication aimed at identifying molecules associated specifically with the pancreatic beta cell, as an mRNA that was more highly expressed in pancreatic beta cells than in alpha cells, liver or kidney Neophytou et al.For more course tutorials visit.
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