Synergistic combined effect between CD40-1C&gt;T and CTLA-4+6230G&gt;A polymorphisms in Graves' disease

Chen, Xiaoming; Hu, Zhuoqing; Li, Wei; Wu, Ping; Liu, Meilian; Bao, Liwen; Wu, Mei‐Hwan; Fang, Shuo; Xiong, Wei; Chen, Manyang; Ge, Wei

doi:10.1016/j.gene.2015.04.074

Cited by 8 publications

(10 citation statements)

References 22 publications

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“…Whether the SNPs negatively affect sufficient thymic expression of self-antigens (TSHR), alter the function of Tregs (FOXP3, CD25), or lower the threshold for T cell activation (CD40, CTLA4, HLA), it is clear that there is ultimately a breakdown in tolerance that tips the balance towards autoimmunity. And evidence suggests that SNPs in more than one susceptibility gene may synergistically shift the balance even further [112]. Understanding the functional and mechanistic consequences of these susceptibility gene variants is essential for the development of new, targeted and preventative therapies for AITD.…”

Section: Discussionmentioning

confidence: 99%

Immunogenetics of autoimmune thyroid diseases: A comprehensive review

Lee

Hammerstad

et al. 2015

Journal of Autoimmunity

298

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Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.

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Section: Discussionmentioning

confidence: 99%

Immunogenetics of autoimmune thyroid diseases: A comprehensive review

Lee

Hammerstad

et al. 2015

Journal of Autoimmunity

298

200

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“…We found that those GD-related SNPs were located at different positions in the CTLA4 region within different populations. The majority of patients with GD from different ethnicities were associated with rs231775 and/or rs3087243 (Polish [37,38], Chinese [39,40,41,42,43,44], Saudi Arabian [45,46], Iranian [47,48], Italian [49], Japanese [50], and Taiwanese [17,18,19]). However, rs733618 and its relationship with GO have been found merely in Taiwan population.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Correlation between Graves’ Ophthalmopathy and CTLA4 Gene Polymorphism

Chen

Chu

Wen

et al. 2019

JCM

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Graves’ disease (GD) is an autoimmune inflammatory disease, and Graves’ ophthalmopathy (GO) occurs in 25–50% of patients with GD. Several susceptible genes were identified to be associated with GO in some genetic analysis studies, including the immune regulatory gene CTLA4. We aimed to find out the correlation of CTLA4 gene polymorphism and GO. A total of 42 participants were enrolled in this study, consisting of 22 patients with GO and 20 healthy controls. Chi-square or Fisher’s exact test were used to appraise the association between Graves’ ophthalmopathy and CTLA4 single nucleotide polymorphisms (SNPs). All regions of CTLA4 including promoter, exon and 3’UTR were investigated. There was no nucleotide substitution in exon 2 and exon 3 of CTLA4 region, and the allele frequencies of CTLA4 polymorphisms had no significant difference between patients with GO and controls. However, the genotype frequency of “TT” genotype in rs733618 significantly differed between patients with GO and healthy controls (OR = 0.421, 95%CI: 0.290–0.611, p = 0.043), and the “CC” and “CT” genotype in rs16840252 were nearly significantly differed in genotype frequency (p = 0.052). Haplotype analysis showed that CTLA4 Crs733618Crs16840252 might increase the risk of GO (OR = 2.375, 95%CI: 1.636–3.448, p = 0.043). In conclusion, CTLA4 Crs733618Crs16840252 was found to be a potential marker for GO, and these haplotypes would be ethnicity-specific. Clinical application of CTLA4 Crs733618Crs16840252 in predicting GO in GD patients may be beneficial.

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“…Similarly, Yang et al [10] also found that there was no multiplied interaction between CD40 C/T (− 1) and CTLA-4 A/G (49) SNPs associated with GD susceptibility. However, another study has shown that there may be a combined and additive effect between the CD40–1C > T and CTLA-4-6230G > A polymorphisms with the development of GD [13]. Other studies have shown that interactions between CTLA-4 and other genes also increased the risk of GD.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that there may be a combined and additive effect between the CD40–1C > T and CTLA-4-6230G > A polymorphisms with the development of GD [13]. Thus, we have combined multiple known polymorphic loci before performing correlation analyses between the haplotypes and GD.…”

Section: Introductionmentioning

confidence: 99%

Correlation between CTLA-4 and CD40 gene polymorphisms and their interaction in graves’ disease in a Chinese Han population

Chen

Liu

et al. 2018

BMC Med Genet

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BackgroundSingle-nucleotide polymorphism (SNP) haplotype and SNP-SNP interactions of CTLA-4 and CD40 genes, with susceptibility to Graves’ disease (GD), were explored in a Chinese Han population.MethodsSNP were genotyped by high resolution melting (HRM). Use the method of Pearson χ2 test and Logistic regression for the association between single SNP and Graves’ disease. Using the method of χ2 test and Multifactor Dimensionality Reduction (MDR) to analysis the haplotype frequency distribution, the interaction of SNPs respectively.ResultsGenotypic and allelic frequencies of SNP rs231775, rs3087243 and rs1883832 were statistically different between controls and GD (p < 0.05). Mutant allelic frequency of G rs231775 was higher, and A and T allelic frequencies of rs3087243 and rs1883832 were lower in GD than in controls (P < 0.05). In CTLA-4 rs1024161, rs5742909, rs231775, rs231777, rs231779, rs3087243 and rs11571319 showed D’ < 50% and r2 < 0.3 among each SNP. We identified six commonly found haplotypes; TCGCTGC was associated with the highest GD risk (OR = 2.565) and TCACTAC the lowest (OR = 0.096). MDR analysis indicated interactions among the rs231775 GG, rs231779 TT and rs3087243 GG genotypes in CTLA-4 might increase GD risk by 2.53-fold (OR = 2.53).ConclusionCTLA-4 and CD40 were associated with GD incidence in a Chinese Han population. The TCGCTGC and TCACTAC haplotypes in the CTLA-4 gene, were risk and protective factors for Graves’disease respectively. Interactions among the SNPs of rs231775, rs231779 and rs3087243 significantly increase the susceptibility to GD.

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Synergistic combined effect between CD40-1C>T and CTLA-4+6230G>A polymorphisms in Graves' disease

Cited by 8 publications

References 22 publications

Immunogenetics of autoimmune thyroid diseases: A comprehensive review

Immunogenetics of autoimmune thyroid diseases: A comprehensive review

Investigation of the Correlation between Graves’ Ophthalmopathy and CTLA4 Gene Polymorphism

Correlation between CTLA-4 and CD40 gene polymorphisms and their interaction in graves’ disease in a Chinese Han population

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