What is the role of genetics in Graves disease?

Updated: Apr 17, 2020
  • Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22. [4] Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. HLA-DRB1 and HLA-DQB1 also appear to be associated with Graves disease susceptibility. Genetic factors contribute approximately 20-30% of overall disease susceptibility.

  • Cytotoxic T lymphocyte-associated molecule-4 (CTLA4) is a major thyroid autoantibody susceptibility gene, [33, 34] and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease. The G allele of exon1 +49 A/G single nucleotide polymorphism (SNP) of the CTLA4 gene influences higher TPOAb and TgAb production in patients who are newly diagnosed with Graves disease. [33] This SNP of the CTLA4 gene can also predict recurrence of Graves disease after cessation of thionamide treatment. [35]

  • There is an association of a C/T SNP in the Kozak sequence of CD40 with Graves disease. [4, 36]

  • The association of SNPs in PTPN22 varies among autoimmune diseases individually or as part of a haplotype, and the mechanisms by which PTPN22 confers susceptibility to Graves disease may differ from other autoimmune diseases. [37]

  • Alleles of intron 7 of the thyrotropin receptor gene (TSHR) have also been shown to contribute to susceptibility to Graves disease.

  • Inhibitory antibodies directed against insulinlike growth factor receptor-1 (IGFR-1) were seen in 14% of patients with Graves ophthalmopathy, but there was no activation of IGFR-1 in association with these antibodies. [38]

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