Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

Abstract

The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G singlenucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P¼0.01, OR¼1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.

Influence of the TSH Receptor Gene on Susceptibility to Graves' Disease and Graves' Ophthalmopathy

“…In our current study and in accordance with previous reports, the TSHR gene intron 1 region was highly associated with GD but not HT, giving an OR of up to 1.8 with TSHR-SNP-rs2268458. This association was similar to that observed in the literature for the CTLA-4 gene (which has averaged an OR of 1.5) (23,24), indicating a modest influence on genetic susceptibility. However, examining TSHR SNP and CTLA-4 susceptibility alleles failed to demonstrate a significant interaction between them although this was restricted to ruling out an OR >2.0.…”

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

“…Therefore, structural heterogeneity of the DR b chain at position 74 may be a predisposing factor for GD only in some at risk individuals and other genes must also play important roles in the susceptibility and initiation of GD. 4 Indeed, additional putative GD susceptibility genes have been recently identified, including CTLA-4, [31][32][33][34] CD40, 35,36 and thyroglobulin. [37][38][39] Patients and methods…”

Immune Profile and Signal Transduction of T-Cell Receptor in Autoimmune Thyroid Diseases

“…The autoimmune thyroid diseases (ATD), such as Hashimoto's thyroiditis and Graves' disease are found in the general population and have an estimated prevalence of 5% (Ban, Davies et al, 2003). Pathogenesis of ATD especially that of GD is brought about by complex interaction between environmental and genetic factors.…”