Do CTLA4 rs231775, SH2B3 rs3184504, and HLA-DQA1 rs2187668 increase autoimmune thyroid risk even when TPO antibodies are negative?

Genetic susceptibility to autoimmune thyroid disease (AITD) and broader systemic autoimmunity is heavily influenced by inherited risk alleles, which can predate the clinical manifestation of autoantibodies.

Clinical evidence and thyroid risk

• Autoimmune Thyroid Disease (AITD): Genetic evidence strongly links CTLA4 rs231775 and SH2B3 rs3184504 to increased risk of Hashimoto's thyroiditis and Graves' disease, with SH2B3 acting as a well-documented locus for hypothyroidism risk.
• Seronegative Susceptibility: Because these genetic variants govern upstream immune activation rather than downstream antibody production, their risk association remains highly plausible even in patients who currently test negative for thyroid peroxidase (TPO) antibodies. Seronegative Hashimoto's is a recognized clinical entity where pathology occurs without detectable TPO antibodies.
• Broad Autoimmune Risk: These three variants act as multi-disease susceptibility loci. For example, HLA-DQA1 rs2187668 tags the highly reactive HLA-DQ2/DR3 haplotype, which is linked to broad autoantibody development and systemic autoimmunity.

Mechanistic pathways

• Impaired Checkpoint Inhibition: The G allele of CTLA4 rs231775 impairs the glycosylation and cell-surface expression of the CTLA-4 checkpoint receptor. This reduction in cell-surface inhibitory signaling prevents the effective downregulation of T cells, driving T-cell hyperreactivity.
• Altered Immune Signaling and Antigen Presentation: The SH2B3 rs3184504 variant disrupts cellular cytokine and lymphocyte signaling. Concurrently, HLA-DQA1 rs2187668 alters class II MHC molecules, which directly dictates how thyroid self-antigens are presented to T cells, initiating the autoimmune cascade.

Bottom line

• The CTLA4 rs231775, SH2B3 rs3184504, and HLA-DQA1 rs2187668 variants are established drivers of systemic and thyroid autoimmunity. Their biological impact on T-cell regulation and antigen presentation makes them plausible indicators of autoimmune thyroid risk even when TPO antibodies are currently negative.