CTLA-4 gene polymorphism associated with Graves' disease in a Caucasian population.

Abstract

Graves' disease (GD) is an autoimmune thyroid disease. Multiple genetic factors are believed to be involved in its pathogenesis, but the factors are largely unknown, except for sex (female disease preponderance) and the role of human leukocyte antigen (HLA) genes on chromosome 6. To understand the mechanisms underlying the development of GD, a search for non-HLA-linked genes is crucial, and we tested several candidate genes, including the CTLA-4 gene on chromosome 2q33. CTLA-4 molecules may either facilitate or down-regulate the second signal to T-cells, which is provided by the interaction between the two accessory molecules CD28 and B7. One hundred and thirty-three Caucasian patients (26 males) with GD and 85 local controls were included in this study. Polymerase chain reaction was used to amplify DNA containing the (AT)n repeat within the 3'-untranslated region of exon 3 of the CTLA-4 gene. The 5'-forward primer was radiolabeled, and amplified products were resolved on 5-7% sequencing gels. All subjects were previously typed for HLA class II alleles. Twenty-one alleles were observed with sizes ranging from 88-134 basepairs. In the association analysis, the genotype frequencies between GD patients and controls differed significantly (P = 0.012), and the difference was attributable to a higher frequency of the 106-basepair allele among patients (relative risk, 2.82). When the patients were subdivided with respect to sex and HLA, the phenotype frequencies of allele 106 was higher in the female patients with protective HLA specificities (DQA1*0201 positive/DQA1*0501 negative) than in those with susceptible HLA specificities (DQA1*0201 negative/DQA1*0501 positive; 81.8% vs. 45.5%; P = 0.026). The CTLA-4 gene or a closely associated gene (including CD28) confers susceptibility to GD. This association may be more important in female patients with protective HLA specificities, who otherwise would be at low risk of developing the disease.

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

“…A distribution analysis of the soluble and full-length CTLA-4 transcripts among the CD4 and CD8 subsets of T cells has demonstrated that CD4 cells express both transcripts at the same level, whereas CD8 cells appear to express nearly 2.5-fold more full-length product with respect to sCTLA-4 [10,20,53]. An analysis of the association between the sCTLA-4 mRNA level and exon 1 +49A/G and CT60A/G CTLA-4 gene polymorphisms in healthy subjects also showed that the sCTLA-4 mRNA level in unstimulated CD4 T cells is higher for allele A at position +49 and the CT60 A variant [29].…”

“…The CTLA4 locus is the only non-HLA locus for which the association with GD has been repeatedly demonstrated since 1995, when the first evidence for an association with the CTLA-4 3′-UTR-microsatellite in a Caucasian population was reported [29]. Linkage and association of the CTLA-4 exon 1 polymorphism with GD, and to lesser extent with HT, has been found in several populations, although there seems to be some inconsistency, probably due to population heterogeneity [11,17,27,[30][31][32][33] (Table 1).…”

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

“…8 There have been several reports demonstrating an association between the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene and the AITDs 6,9-25 ( Table 1). The association between GD and a CTLA-4 3 0 untranslated region (3 0 UTR) microsatellite (AT repeat) and an A/G single-nucleotide polymorphism (SNP) at position 49 in the CTLA-4 leader peptide (A/G 49 ) has been consistent across populations of different ethnic backgrounds, such as Caucasians, 6,9,10,[14][15][16][17] Chinese, 11 Japanese, 13,22 and Koreans. 23 The association of CTLA-4 and GD has also been confirmed in a family-based study using transmission disequilibrium test (TDT) analysis.…”

New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus

“…9 Furthermore, B7 blockage using anti-B7 antibodies or CTLA-4Ig can prevent the development of murine experimental autoimmune encephalomyelitis (EAE), a T cellmediated autoimmune disease that shares many clinical and histological features with human MS. [10][11][12][13] It was considered possible that structural variations as well as the dysregulation in the expression of the costimulatory molecules may be associated with susceptibility to autoimmune or chronic inflammatory diseases. It was reported that polymorphism within CTLA-4 exon 1 (49A/G) and that of the dinucleotide repeats within 3′-untranslated region (3′-UTR) seemed to be significantly associated with insulin-dependent diabetes mellitus (IDDM), 14,15 Graves' disease 16,17 or Hashimoto's thyroiditis. 18 Moreover, a genome-wide linkage study reported 2q33 and 3q13 as candidate chromosomal regions for rheumatoid arthritis (RA), which are adjacent to the loci where CD28 and CTLA-4, CD80 and CD86 are localized, respectively.…”