Gene Polymorphisms for Both Auto-antigen and Immune-Modulating Proteins Are Associated with the Susceptibility of Autoimmune Myasthenia Gravis

Li, Haifeng; Hong, Yu; Zhang, Xu; Xie, Yanyan; Skeie, Geir; Hao, Hongjun; Gilhus, Nils Erik; Liang, Bing; Yue, Yao-Xian; Zhang, Xianjun; Gao, Xiang; Wang, Qi; Gao, Zhe; Ding, Xiaojun; Song, Min Seob

doi:10.1007/s12035-016-0024-y

Cited by 16 publications

(12 citation statements)

References 36 publications

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“…Relating to our findings previous studies identified CTLA4 SNP rs733618 to be significantly associated with myasthenia gravis [ 23 , 24 , 25 ]. An association with PBC or PSC and rs733618 has not been demonstrated yet.…”

Section: Discussionsupporting

confidence: 91%

CTLA-4 Expression Plays a Role in PSC and PBC Progression

et al. 2020

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Background & Aims: The pathogenesis of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) remains unclear. The aim of this study was to reveal certain single nucleotide polymorphisms (SNP) in genes for regulatory proteins in the immunologic pathway possibly going along with susceptibility of attaining PBC or PSC. Methods: 126 patients with either PBC or PSC with clinical and laboratory data were enrolled in the study. SNPs in three genes (CTLA-4, ICOS, and FOX-P3) which are suspected to play a key role in the autoimmune pathway were analyzed to determine allele variants. Gene expression was measured by RealTime PCR using mRNA. Results: Patients with cirrhosis had a lower number of CTLA-4 copies than patients without cirrhosis (p = 0.04). Accordingly, patients with lower CTLA-4 copies had a poorer recovery of gamma-glutamyltransferase (GGT) in course of their disease (−69.8 U/l vs. −176.1 U/l p = 0.04). Two SNP allele variants (CTLA4 rs733618 and FOXP3 rs2280883) associated with low CTLA-4 expression could be determined. Patients having both variants showed worsening of GGT (−61.7 U/l vs. −132.6 U/l, p = 0.04) and a trend towards a more progressive disease in terms of cirrhosis. (24% vs. 13% p = ns). Conclusions: Low expression of CTLA-4 is associated with a more advanced disease in patients with PBC and PSC. Furthermore, we identified two SNP allele variants (CTLA4-SNP rs733618 and FOXP3-SNP rs2280883) associated with a lower CTLA-4 expression and possibly a more severe course of the diseases. Taken together, these results provide further evidence for the involvement of the immune system in the pathogenesis of these two cholestatic liver diseases. Lay summary: Primary biliary cholangitis and primary sclerosing cholangitis are chronic diseases of the bile ducts. Their cause remains widely unclear, but evidence suggests the immune system plays a central role. This study shows that gene alterations connected to the immune system might play a role in the course of the disease.

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Section: Discussionsupporting

confidence: 91%

CTLA-4 Expression Plays a Role in PSC and PBC Progression

et al. 2020

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“…Genetic variant of CTLA‐4 has been initially found to be associated with MG in Caucasians (Huang et al., ), followed by extensive investigations of association of single nucleotide polymorphisms (SNPs) in such locus with MG (Wang et al., ; Wang, Pirskanen, Giscombe, & Lefvert, ). More recent studies have reported predisposing effects of CTLA‐4 polymorphisms on MG in other Western and Asian populations (Chuang et al., ; Li et al., ; Sun et al., ). Summing up the literature, the five most common CTLA‐4 SNPs—positions –1722 (C/T, rs733618), –1661 (A/G, rs4553808), and ‐318 (C/T, rs5742909) of the promoter region, position +49 (A/G, rs231775) of exon 1, and position CT60 (A/G, rs3087243) of the 3′‐untranslated region—have been observed among different ethnic groups, demonstrating somehow inconsistent results.…”

Section: Introductionmentioning

confidence: 99%

Association of CTLA‐4 polymorphisms with increased risks of myasthenia gravis

Yuan

2018

Annals of Human Genetics

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Myasthenia gravis (MG) is considered to be a kind of autoimmune disorder resulting from dysfunction of neuromuscular transmission caused by autoantibodies against the nicotinic acetylcholine receptors. A number of studies have identified Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) as a candidate gene for MG. Several recent reports have indicated that single nucleotide polymorphisms (SNPs) of CTLA-4, including rs733618, rs4553808, rs5742909, rs231775, and rs3087243 were associated with the risks of MG; however, the results were not consistent. To assess the correlations between CTLA-4 SNPs and MG susceptibility, a meta-analysis was performed following a series of database searching. A total of 1460 cases and 1652 controls from 12 studies were enrolled in the analysis. Our results indicated that rs231775 and rs733618 were associated with higher risks of MG, providing potential references for future case-control studies.

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“…Investigation of rs733618 and rs16840252 in T cell activation would uncover the underlying mechanism in development of GO. In Table 6, disease association of rs733618 [23,27,28,29,30,31,32,33,34] and rs16840252 [35,36] were summarized.…”

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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Gene Polymorphisms for Both Auto-antigen and Immune-Modulating Proteins Are Associated with the Susceptibility of Autoimmune Myasthenia Gravis

Cited by 16 publications

References 36 publications

CTLA-4 Expression Plays a Role in PSC and PBC Progression

CTLA-4 Expression Plays a Role in PSC and PBC Progression

Association of CTLA‐4 polymorphisms with increased risks of myasthenia gravis

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

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