Immunogenetic Mechanisms Leading to Thyroid Autoimmunity: Recent Advances in Identifying Susceptibility Genes and Regions

Abstract

The autoimmune thyroid diseases (AITD) include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.

Sequential elevation of autoantibodies to thyroglobulin and glutamic acid decarboxylase in type 1 diabetes

“…However, it has been reported that female gender, older (adolescence) onset, longer duration of diabetes, and positivity for GADA were risk factors for the development of thyroid disorders [3,5] . In addition, it is generally accepted that a certain type of HLA is involved in the development of type 1 diabetes and AITD [13,14] .…”

Changes in Serum Adhesion Molecules, Chemokines, Cytokines, and Tissue Remodeling Factors in Euthyroid Women Without Thyroid Antibodies Who Are at Risk for Autoimmune Thyroid Disease: A Hypothesis on the Early Phases of the Endocrine Autoimmune Reaction

“…Markers to predict the risk for AITD in very early stages of the autoimmune disease and before TPO-Abs are detectable in serum are limited and comprise the genetic polymorphisms of immune-related genes (major histocompatibility complex class II molecules, cytotoxic T-lymphocyte antigen 4, protein tyrosine phosphatase, non-receptor type 22) and genes related to thyroid antigens (the TSH receptor and thyroglobulin) (1,8). For this study we hypothesized that other early prediction markers might be found in a set of molecules related to the accumulation and activation of macrophages and dendritic cells (DCs) in the thyroid gland just prior to thyroid autoimmunization.…”

TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves’ disease and Graves’ ophthalmopathy

“…Previous studies recently demonstrated that intronic polymorphisms have gained attention, especially because of their possible roles in the regulation of TSHR expression [16,[28][29][30][31][32]. Intronic polymorphisms are responsible for generation of different receptors forms [12].…”