Are CTLA4 rs231775 and CD40 rs1883832 variants associated with autoimmune thyroid disease?

Genetic variations in immune checkpoint and costimulatory pathways are pivotal in the pathogenesis of autoimmune thyroid diseases (AITD), primarily Graves' disease.

Clinical association evidence

• CTLA4 rs231775: The CTLA4 rs231775 (+49 A/G) G allele and GG genotype are strongly associated with susceptibility to Graves' disease, particularly in East Asian populations. In contrast, its association with Hashimoto's thyroiditis remains highly heterogeneous.
• CD40 rs1883832: The CD40 rs1883832 (-1 C/T) C allele is a robust risk modifier for Graves' disease, with homozygous CC carriers exhibiting a 1.5- to 2-fold higher risk of disease and elevated thyroid-stimulating hormone receptor antibodies. This variant has no significant association with Hashimoto's thyroiditis.

Mechanistic pathways

• T-cell checkpoint inhibition: The CTLA4 rs231775 G allele encodes a threonine-to-alanine substitution in the leader signal peptide, impairing endoplasmic reticulum processing and glycosylation. This reduces cell-surface CTLA-4 density, weakening the inhibitory checkpoint brake (CD28-CTLA-4-B7 axis) and permitting autoreactive T-cell activation against thyroid tissue.
• B-cell costimulation: The CD40 rs1883832 polymorphism sits at the -1 position of the Kozak consensus sequence, directly modulating translation efficiency. The T allele reduces CD40 translation, resulting in lower surface expression of CD40 on B cells. This alters CD40-CD40L costimulatory signaling, which influences B-cell activation, immunoglobulin class switching, and the production of autoantibodies targeting thyroid enzymes.

Bottom line

• The CTLA4 rs231775 and CD40 rs1883832 variants compromise immune homeostasis by impairing T-cell inhibitory thresholds and tuning B-cell costimulation, jointly driving susceptibility to autoimmune thyroid disease, especially Graves' disease.