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.

Ctla-4 Gene Polymorphism in Relation to Thyroid Disorders in Patients With Chronic Hepatitis C Under Interferon Alpha Therapy

“…In accordance with our results, studies conducted among different populations showed an association of CTLA-4 gene 49 A/G polymorphism with Graves' disease including Caucasians (Yanagawa et al, 1995), Japanese (Yanagawa et al, 1997), Koreans (Park et al, 2000), Chinese children (Chong et al, 2008) and Taiwanese (Weng et al, 2005) and in South Indian population (Veeramuthumari et al, 2011). However, the study of Frydecka et al (2004), showed that the distribution of CTLA-4 exon 1 A (49)G genotype, allele and phenotypic frequencies did not differ between patients with GD and healthy subjects in Polish population.…”

“…This can be added to the results of other studies in which the distribution of genotypes (GG, AG and AA) for CTLA-4 gene polymorphism varies among different populations including Caucasians (Yanagawa et al, 1995), Japanese (Yanagawa et al, 1997), Koreans (Park et al, 2000), Hong Kong Chinese children (Chong et al, 2008) and Taiwanese (Weng et al, 2005).…”

“…The first of these reports was made by Yanagawa et al (1995), who found a significant association between variation in the (AT) dinucleotide repeat within the 3'-untranslated region of the CTLA-4 gene and the presence of Grave's Disease (GD). Subsequent to these findings, many others have reported associations between SNPs within and around the CLTA-4 region and rheumatoid arthritis (Lei et al, 2005), celiac disease (Hunt et al, 2005), type I diabetes (Jung et al, 2009), myasthenia gravis (Wang et al, 2008) and autoimmune pancreatitis (Chang et al, 2007).…”

Association of HLA-DR, -DQ Genotype and CTLA-4 Gene Polymorphism with Graves’ Disease in Japanese Children

“…The development of GD is thought to be determined by genetic and environmental factors, and in terms of genetic factors, GD has been documented to be associated with human leukocyte antigen (HLA) on chromosome 6p [2] and cytotoxic T lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 [3]. …”

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment

“…As matter of fact, the association with HLA class Ⅱ molecules, the concordance studies in twins, the association with CTLA-4 and protein tyrosine phosphatase nonreceptor-type 22 and CD40 polymorphism (A/G49 and 1858C/T and CC genotype, respectively), the association of a microsatellite inside the FoxP3 gene, the linkage with chromosomal locations (14q31, 18q21, 20q11, Xp11, Xq21, 6p, 13q32 and 12q22) and the presence of anti-thyroid Abs in siblings of probands with AITD have been observed [23][24][25][26][27][28][29][30][31][32] . Moreover, the HLA class Ⅱ (DRB1*0301) is also associated with chronic HCV infection [33] .…”