Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics

Abstract

Recent advances in our understanding of genetic-epigenetic interactions have unraveled new mechanisms underlying the etiology of complex autoimmune diseases. Autoimmune thyroid diseases (AITDs) are highly prevalent, affecting 1% to 5% of the population. The major AITDs include Graves disease (GD) and Hashimoto's thyroiditis (HT); although these diseases contrast clinically, their pathogenesis involves shared immunogenetic mechanisms. Genetic data point to the involvement of both shared and unique genes. Among the shared susceptibility genes, HLA-DRβ1-Arg74 (human leukocyte antigen DR containing an arginine at position β74) confers the strongest risk. Recent genome-wide analyses have revealed new putative candidate genes. Epigenetic modulation is emerging as a major mechanism by which environmental factors interact with AITD susceptibility genes. Dissecting the genetic-epigenetic interactions underlying the pathogenesis of AITD is essential to uncover new therapeutic targets.

Figure 1

A Venn diagram showing susceptibility genes for AITD. Most genes are common to both GD and HT while several are unique to GD and HT. Additional genes are likely associated with AITD as demonstrated by recent GWAS and immunochip studies (see text).

Figure 2

Genetic risk alone can confer a moderate risk, but this risk is amplified when combined with synergistic epigenetic modifications of regulatory regions controlling gene expression.