Yaron Tomer, MD
Our laboratory is studying the genetic etiology of autoimmune thyroiditis and autoimmune diabetes. Genetic studies in autoimmune thyroid diseases. There is solid epidemiologic data supporting a major role for genetic predisposition in the development of autoimmune thyroid diseases (AITDs). Our goals are to identify the susceptibility genes predisposing to AITD. We are utilizing modern genetic, genomic, and bioinformatic techniques to discover the susceptibility genes for AITD. Some of the methods we are using include whole genome linkage studies, linkage disequilibrium mapping, single nucleotide polymorphism (SNP) discovery and analysis, and functional genomic techniques. A whole genome screen in 102 families enabled us to map 8 genetic regions harboring AITD genes. In two of these regions we identified new AITD susceptibility genes: (1) the CD40 gene (on chromosome 20); CD 40 is an important immune regulator of B-cell responses, and we identified a single nucleotide polymorphism in the Kozak sequence of CD40 that predisposes to thyroid autoimmunity. (2) the thyroglobulin gene (on chromosome 8); amino acid substitutions were identified in thyroglobulin that are associated with the development of thyroiditis in humans and in mice. The sequence variants identified in these two genes are now being studied in order to understand how they affect the function of these genes in a way that confers susceptibility to AITD. In addition, the other genetic regions identified are being fine mapped and positional candidate genes are being sequenced. Genetic analysis of autoimmune (juvenile) diabetes and thyroiditis. There is a well known genetic association between autoimmune (juvenile) diabetes and thyroiditis (AITD). Both diseases frequently cluster in families together, and can even occur in the same individual. However, no studies have examined the genetic relationship between autoimmune diabetes and AITD. Our goals are to identify the joint susceptibility genes for autoimmune diabetes and AITD. We have obtained DNA samples from a unique set of families in which both autoimmune diabetes and thyroiditis cluster. These families are uniquely suited to study the joint susceptibility genes for autoimmune diabetes and thyroiditis because these genes are highly penetrant in these families. We are beginning a whole genome screening in these families which will lead to the identification of genetic regions harboring susceptibility genes common to these two diseases. We will then proceed with fine mapping and sequencing studies to identify the joint susceptibility genes for autoimmune diabetes and thyroiditis. These genes are of major importance for researchers studying autoimmunity because they most likely predispose to autoimmunity in general and not only to one particular autoimmune disease. HLA and thyroid autoimmunity. The HLA genes play a central role in presentation of peptides to T-lymphocytes. It is well known that certain HLA alleles, specifically DR3, are associated with thyroid autoimmunity. We have recently discovered that a certain amino acid in the peptide binding groove of HLA is critical for disease susceptibility. We are now conducting functional-structural studies, in collaboration with Dr. Osman's group from the department of biophysics in order to elucidate how this amino acid substitution changes the structure of the HLA molecule in a way that enables it to present self-peptides to T-lymphocytes and to initiate autoimmunity.