Our goals are to identify and characterize the susceptibility genes for autoimmune thyroid diseases (AITD), Graves'disease (GD) and Hashimoto's thyroiditis (HT), and to dissect the genetic-epigenetic causes of thyroid autoimmunity. In the last grant cycle, we made substantial progress toward these goals: (1) We fine mapped loci linked with AITD and identified 2 new AITD genes: ARID5B and NRXN3;we also identified new genes associated with distinct subsets of AITD;(2) We discovered that arginine at position 74 of the DRb1chain is key to susceptibility to AITD;(3) We found that a GD-associated TSHR variant in intron 1 down regulated TSHR transcription by epigenetic interaction with the transcription factor PLZF;(4) We identified a thyroglobulin (Tg) promoter variant that predisposes to AITD, and showed that the risk allele interacted epigenetically with IRF-1 to modify histone signatures;(5) We defined CD40 as a major GD susceptibility gene and demonstrated that the susceptible allele increased thyroidal expression of CD40 triggering GD via activation of IL-6. Following these discoveries our hypothesis is that susceptibility genes trigger AITD through alterations in gene expression and/or function as a result of genetic-epigenetic interactions.
Our specific aims are:
Specific Aim 1 : To identify rare genetic variants causing AITD by performing next generation sequencing (NGS) in our unique dataset of 102 multiplex AITD families that are enriched with such variants. We will perform NGS on 2 previously replicated linked loci (10q and 14q) in members of linked families. We will use structural modeling to identify variants predicted to alter gene function/expression;these selected variants will be tested in a large cohort of AITD patients and controls.
Specific Aim 2 : To dissect genetic-epigenetic interactions of AITD genes with interferon alpha (IFNa). We will test the hypothesis that genetic-epigenetic interactions between a thyroglobulin (Tg) promoter SNP and IFNa trigger AITD by accelerating Tg synthesis and inducing ER stress. We will also test if a TSHR intron 1 SNP predisposes to GD by facilitating binding of PLZF to intron 1 thereby decreasing thymic TSHR synthesis, leading to escape from central tolerance.
Specific Aim 3 : We will test the hypothesis that a CD40 Kozak SNP predisposes to GD by upregulating CD40 expression in the thyroid when there is local thyroidal inflammation. We will also dissect the CD40 signaling pathways in thyroid cells, and translate these findings into new therapies for murine GD using CD40 blockade. In summary, our project builds directly on the knowledge gained in the last grant period, and focuses on 3 AITD genes that we and others identified, Tg, TSHR, and CD40. We now propose to move from gene-discovery to functional analyses and to dissect the mechanisms by which these genes trigger AITD. Our multidisciplinary team has the experience and expertise to achieve our aims. Our functional studies will unravel the molecular mechanisms causing AITD. It is the understanding of these mechanisms that will lead to translational research testing novel, mechanism-based, treatment and prevention strategies such as cytokine and CD40 blockade.
Autoimmune thyroid diseases (AITD), including Graves'disease and Hashimoto's thyroiditis are complex diseases caused by an interaction between susceptibility genes and environmental triggers. The overall goal of our studies is to identify and characterize the susceptibility genes for AITD and to analyze the genetic- environmental interactions that cause disease. Understanding the molecular mechanisms causing AITD will lead to the development of novel therapeutic and prevention approaches to AITD.
|Li, Cheuk Wun; Osman, Roman; Menconi, Francesca et al. (2016) Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes. J Autoimmun :|
|Li, Cheuk Wun; Menconi, Francesca; Osman, Roman et al. (2016) Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis. J Biol Chem 291:4079-90|
|Lee, Hanna J; Li, Cheuk Wun; Hammerstad, Sara Salehi et al. (2015) Immunogenetics of autoimmune thyroid diseases: A comprehensive review. J Autoimmun 64:82-90|
|Lombardi, Angela; Inabnet 3rd, William Barlow; Owen, Randall et al. (2015) Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis. J Clin Endocrinol Metab 100:E1-10|
|Lipner, Ettie M; Tomer, Yaron; Noble, Janelle A et al. (2015) Linkage Analysis of Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications and Interaction with HLA. J Diabetes Res 2015:694107|
|Li, Cheuk Wun; Concepcion, Erlinda; Tomer, Yaron (2015) Dissecting the role of the FOXP3 gene in the joint genetic susceptibility to autoimmune thyroiditis and diabetes: a genetic and functional analysis. Gene 556:142-8|
|Tomer, Yaron; Dolan, Lawrence M; Kahaly, George et al. (2015) Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. J Autoimmun 60:32-9|
|Stefan, Mihaela; Zhang, Weijia; Concepcion, Erlinda et al. (2014) DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun 50:33-7|
|Tomer, Yaron (2014) Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics. Annu Rev Pathol 9:147-56|
|Stefan, Mihaela; Wei, Chengguo; Lombardi, Angela et al. (2014) Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity. Proc Natl Acad Sci U S A 111:12562-7|
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