Identifying Genes Linked to Autoimmune Thyroid Diseases

Project: Research project

Project Details

Description

DESCRIPTION: (provided by applicant) The autoimmune thyroid diseases (AITD) are
very common with a prevalence of - 5 percent. They include Hashimoto's
thyroiditis (HT), which manifests by hypothyroidism, and Graves disease (GD),
which causes hyperthyroidism. The mechanisms initiating the AITD are not
completely understood. Abundant data point to a genetic susceptibility to AITD,
and the applicant, has identified linkages for several AITD susceptibility
loci. In the past four years we have performed genome scans on two data sets of
multiplex families (102 families, 540 individuals), and mapped 8 loci showing
evidence for linkage with AITD. In two of the loci we identified and
investigated putative AITD susceptibility genes (CTLA-4 and CD4O}. The focus of
the current proposal is four of the eight loci which showed the strongest
evidence for linkage with AITD. The goals of our study are to identify and
characterize the AITD susceptibility genes in these four loci. The specific
aims of the proposed study are: 1) To resolve the genetic heterogeneity in our
families at the 4 linked loci which are the focus of our studies. At all 4 loci
the linkage analysis showed evidence of heterogeneity and resolving it will
facilitate identification of the AITD susceptibility genes. We will subdivide
the families according to various parameters (e.g. age of onset of disease),
analyze these subsets separately for linkage with the four loci, and apply the
Predivided-Sample Test. Resolving heterogeneity and identifying subsets of
families that are uniformly linked with these loci will amplify the power of
the subsequent single nucleotide polymorphism (SNP) and fine mapping analyses
(Specific Aims 2 & 3); 2) To analyze two important genes (thyroglobulin and
TGFBeta3 which are located at 2 of the linked loci, and are themselves linked
and associated with AITD. We will analyze the sequences of the thyroglobulin
and TGF-Beta3 genes in order to identify disease-specific SNP's; 3) To fine map
two additional linked loci and narrow the linked regions in order to determine
appropriate candidate genes for future analyses. We have the capacity and
experience to perform these studies. Our flexible relational database
(lngresTM) facilitates complex linkage and association analyses. We use two
ABI-310 sequencers for genotyping and sequencing, and we have experience at
SNPing genes and fine mapping linked regions. We expect that these studies will
lead to the identification of gene sequence variations contributing to the
expression of AITD. This will allow us to understand the mechanisms initiating
these diseases, and hopefully will lead to the development of new therapies
targeted at the mechanisms initiating AITD.
StatusFinished
Effective start/end date7/1/026/30/03

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $323,745.00

ASJC

  • Genetics(clinical)
  • Genetics
  • Endocrinology
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

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