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.
Highlights
The complete spectrum of autoimmune diseases affect the majority of tissues within the body, including, for example, pancreatic beta cells in type 1 diabetes (T1D), synovial joint antigens in Rheumatoid Arthritis (RA) and myelin surrounding nerve axons in Multiple sclerosis (MS) [1, 2]
The epidemiology varies according to individual conditions, collectively, autoimmune prevalence is at least 5% in the general population and is one of the major causes of premature mortality in young and middle aged women [2, 3]
By far the most common are the autoimmune thyroid diseases (AITDs) [2, 4], which include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), both characterised by lymphocytic infiltration of the thyroid with autoantibodies targeting thyroid antigens, including thyroid peroxidise, thyroglobulin (Tg) and the thyroid stimulating hormone receptor (TSHR) [5, 6]
Summary
The complete spectrum of autoimmune diseases affect the majority of tissues within the body, including, for example, pancreatic beta cells in type 1 diabetes (T1D), synovial joint antigens in Rheumatoid Arthritis (RA) and myelin surrounding nerve axons in Multiple sclerosis (MS) [1, 2]. Chromosome 5q31-q33 identified by independent linkage studies in Japanese and Chinese cohorts represented the most convincing evidence that an AITD predisposing gene might be located within the region [19, 20]. Association studies inherently have greater power to detect a disease-risk gene, since greater numbers of SNPs. 528 Current Genomics, 2011, Vol 12, No 8 can be investigated in a single region and large, wellpowered case-control cohorts are more collected. Numerous SNP associations were identified, with SNPs rs179247 and rs12101255 demonstrating strongest evidence of association with GD, and which are located within a distinct 40Kb of TSHR intron 1 [58] These variants have since been further replicated in independent UK and Polish case-control cohorts (P=10-15 – 10-21 and odds ratios (OR) = 1.38 – 1.87), with logistic regression suggesting that the aetiological variant is most likely to be in strong LD with rs12101255 [50] (Fig. 2). Strongest GD associations were identified within the HLA-region (P
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