Summary
This paper looked at the genetics of patients with either Hashimoto’s Thyroiditis or Graves’ Disease. Both of these diseases are currently thought to autoimmune disorders, like type II diabetes or allergies. Specifically, in thyroid disease, the body produces an “wrong” antibody that, when circulating in the blood, can bind to the surface of thyroid gland cells. Normally, Thyroid Stimulating Hormone (TSH) would beind to these receptor cells and cause the thyroid to produce thyroid hormone. The specificity should be like a lock and key. However, in thyroid disease, it is thought that the body produces an antibody that is similar enough to the TSH “key” to work in the receptor “lock”, thereby confusing the thyroid into producing more thyroid hormone, even when there is no TSH around.
The authors of this paper looked at the gene for the TSH receptor (TSHR) in thyroid patients to see if there were any known genetic places that would cause this. They found 28 places that were “associated” with Grave’s disease – meaning that some GD patients had that particular variation in that location. However, there was a lot of variability in the data. Some GD patients had none of the variants, while some normal people had several. The authors talk about how this is typical of diseases with a genetic component. When you actually dig down to see what cellular changes happen as a result of the genetic difference, the results are muddied.
The upshot? Don’t look for a genetic test for GD anytime soon, and a multitude of factors, not just genetics, determines who develops symptomatic GD.
Reference:
Brand, O.J., Barrett, J.C., Simmonds, M.J., Newby, P.R., McCabe, C.J., Bruce, C.K., Kysela, B., Carr-Smith, J.D., Brix, T., Hunt, P.J., Wiersinga, W.M., Hegedus, L., Connell, J., Wass, J.A., Franklyn, J.A., Weetman, A.P., Heward, J.M. & Gough, S.C. (2009) Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves’ disease. Hum. Mol. Genet., 18, 1704-1713.
Abstract: Graves’ disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclu- sive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (x2 = 32.45, P = 8.90 3 1028, OR = 1.53, 95% CI = 1.32–1.78) and rs12101255 (x2 = 30.91, P = 1.95 3 1027, OR = 1.55, 95% CI=1.33–1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 3 1024). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.
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