The common −318C/T polymorphism in the promoter region of CTLA4 gene is associated with reduced risk of ophthalmopathy in Chinese Graves’ patients

Abstract

Studies in the past have clearly established that CTLA4 is a susceptible gene for Graves' disease (GD). However, association studies between CTLA4 and the risk of developing Graves' ophthalmopathy (GO) in GD patients have shown conflicting results. In this study, associations of five CTLA4 single nucleotide polymorphisms (-1722A/G, -1661A/G, -318C/T, +49G/A, CT60) with GD risk and GO susceptibility in GD patients were investigated in a Chinese population. Our results showed that either +49A/G or CT60 polymorphism was associated with GD susceptibility in the Chinese population. Significant differences in the distribution of the genotypes or alleles evaluated between GD patients with and without clinically evident GO were only found for -318C/T polymorphism (P = 0.03). Multiple logistic regressions revealed that the -318T allele was negatively associated with GO under both additive and dominant genetic models (adjusted OR = 0.56, 95%CI 0.35-0.89, P = 0.014; adjusted OR = 0.51, 95%CI 0.30-0.84, P = 0.009, respectively). Stratification analysis according to gender demonstrated different scenarios concerning the role of the -318T allele in GO risk: a significant protective role for GO was only confirmed in male but not in female GD patients. Haplotype analyses showed that only the haplotypes containing the -318T allele played a protective role in GO. In conclusion, results from this study suggested that the -318T allele might play a protective role in GO susceptibility for GD patients at least in the Chinese population. However, extended analyses with larger sample size should be carried out in patients from different ethnic origins to further verify this association.

Association of CTLA-4 gene polymorphisms −318C/T and +49A/G and Hashimoto's thyroidits in Zahedan, Iran

“…Carriers of the T allele showed a marked enhancement of CTLA-4 mRNA expression and consequently, more expression of CTLA-4 protein on the cell surface (7). To date, only few studies have examined this variation and their results are contradictory: While certain studies have identified a correlation between the +49A/G SNP of CTLA-4 and autoimmune diseases [systemic sclerosis in Italy (36) and rheumatoid arthritis in Mexico (37)], others studies on other populations did not show any association of CTLA-4 SNPs with autoimmune thyroid diseases or other autoimmune conditions (38)(39)(40)(41).…”

Association of CTLA4 and TNF gene polymorphisms with endocrine ophthalmopathy in ethnic Russian patients with Graves’ disease

“…Поскольку инфильтрация ретробульбарных тканей Т-клетками играет ключевую роль в патогенезе ЭОП, ген CTLA4 может рассматриваться в качестве гена-кандидата, предрасполагающего к развитию ЭОП. Изуче-ние ассоциации полиморфных маркеров гена CTLA4 с риском развития ЭОП являлось предметом нескольких исследований в различных популяциях, в некоторых [12][13][14][15][16][17], но не во всех исследованиях [18][19][20][21][22][23] обнаружена ас-социация с ЭОП.…”

Lack of Association between Cytotoxic T-Lymphocyte Antigen-4 −318C/T Polymorphism and Cancer Risk: A Meta-Analysis of Case-Control Studies

“…A report suggested that CTLA-4 contributes directly to the regulation of B-cell responses, since B-cells express CTLA-4 after cell-cell contact with activated T-cells (43). Some reports have suggested that the -318C/T allele may contribute to up regulation of CTLA-4 expression, play a protective role in autoimmune disease (17,19) and may therefore represent one mechanism that inhibits exaggerated immune activity (44). Since the CTLA-4 gene product has inhibitory effects on the immune system, any variation in its expression or function may lead to the breakdown of the delicate homeostasis of this system.…”

“…Individuals carrying the thymine at position -318 and homozygous for adenine at position 49 showed significantly increased expression of both CTLA-4 mRNA and cell surface CTLA-4 (17). Furthermore, previous studies have extensively examined the association of polymorphisms with CTLA-4 susceptibility to autoimmune disorders including Graves' disease, Hashimoto's thyroiditis, systemiclupus erythematosus, and type I diabetes (18,19). Recent reports also revealed that these polymorphisms may influence the ability of CTLA-4 to bind with B-7 cells and subsequently may affect T-cell activation (20,21).…”