Allelic effects on gene regulation at the autoimmunity-predisposing CTLA4 locus: a re-evaluation of the 3′ +6230G&gt;A polymorphism

Anjos, Suzana M.; Shao, Wenlin; Marchand, Luc; Polychronakos, Constantin

doi:10.1038/sj.gene.6364211

Cited by 43 publications

(28 citation statements)

References 22 publications

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“…Atabani and colleagues (6) confirmed this observation in their study of CTLA4 isoforms in purified T cells and demonstrated an association of CT60 and sCTLA4 mRNA levels with the frequency of CD4 ϩ CD25 ϩ regulatory T cells in healthy human volunteers. Importantly, the genotype-dependent difference in the expression of soluble CTLA4 transcripts may be T cell-specific because it is not observed when steady-state CTLA4 mRNA from peripheral blood mononuclear cells, rather than purified T cells, are studied (23). The orthologous CTLA4 region in the mouse also is associated with autoimmune diabetes in the NOD mouse.…”

Section: Discussionmentioning

confidence: 99%

Allelic variant inCTLA4alters T cell phosphorylation patterns

Maier

Anderson

Jager

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Little is known regarding the functional effects of common autoimmune susceptibility variants on human immune cells. The SNP CT60 (rs3087243; A/G) located in the 3 UTR of the CTLA4 gene has been associated with autoimmune diseases. We examined a cohort of healthy individuals stratified by genotypes at CTLA4 to gain insight into the functional effects of allelic variation on T cell signaling. Using phospho-site-specific mAbs, we tested the hypothesis that the CT60 genotype at CTLA4 is associated with altered T cell antigen receptor (TCR) signaling in naive and/or memory T cells. By normalizing for the extent of the initial TCR signaling event at CD3 , we observed that the relative responsiveness to TCR stimulation as assessed by phosphorylation levels of downstream signaling molecules was altered in naive (CD4 ؉ CD45RA high ) and memory (CD4 ؉ CD45RA low ) T cells obtained from individuals with the disease-susceptibility allele at CTLA4. Thus, allelic variation associated with autoimmune disease can alter the signaling threshold of CD4 ؉ T cells. These experiments provide a rational approach for the dissection of T cell-susceptibility genes in autoimmune diseases.genotype ͉ human ͉ T cell antigen receptor signaling ͉ CTLA4 ͉ autoimmunity T he recent successful completion of several genome-wide association scans, together with the rapid advancement in highthroughput genotyping technologies, have resulted in the discovery of an ever-increasing number of genetic variants associated with susceptibility to human autoimmune diseases (1-5). However, because of the small genetic effects of these variants, compared with the strong genetic effects seen in Mendelian diseases, the study of genotypic variation in relation to phenotypes has been a substantial challenge. One well validated region associated with susceptibility to autoimmune disease harbors the CTLA4 gene on chromosome 2q33. An associated allele in this susceptibility region is the G allele of the SNP CT60 (rs3087243; A/G) in the CTLA4 gene region, which has been associated with risk to type 1 diabetes, Graves disease, autoimmune hypothyroidism, systemic lupus erythematosus, and Addison's disease (6-10).The expression of mRNA isoforms of CTLA4 has been investigated in relation to CTLA4 genotype in healthy controls. Moreover, the genotype-dependent difference in the expression of soluble CTLA4 transcripts appears to be T cell-specific (6, 10). In the nonobese diabetic (NOD) mouse, the orthologous CTLA4 region also is associated with autoimmune diabetes, and, similar to humans, an allelic variant causes the increased expression of a major splice isoform. In the NOD model, the isoform is ligandindependent CTLA-4 (11) and results in strongly inhibited T cell responses, as well as increased susceptibility to disease (12). Together these investigations in both the experimental model and in humans suggest that genetic variation in the CTLA4 gene region may have an important effect on T cell function because of altered T cell signaling.Although CTLA4 is important in aut...

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Section: Discussionmentioning

confidence: 99%

Allelic variant inCTLA4alters T cell phosphorylation patterns

Maier

Anderson

Jager

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…The ratio of sCTLA4 to flCTLA4 mRNA splice forms in unstimulated CD4 T cells was 50% lower in +6230G/G positive disease-susceptible individuals compared with A/A protected individuals, suggesting that this 6.1kb region determines splicing efficiency and production of sCTLA4, with the +6230G disease-susceptibility haplotype producing less sCTLA4 transcripts than the +6230A haplotype. However, Anjos et al (33) reported no observable effect of the +6230 SNP on the expression of either sCTLA4 or flCTLA4 using allele-specific single-nucleotide primer extensions. We also failed to find a correlation between +6230 alleles and serum sCTLA4 levels, regardless of susceptibility to AIP in +6230G/G.…”

Section: Discussionmentioning

confidence: 99%

Association of Autoimmune Pancreatitis With Cytotoxic T-lymphocyte Antigen 4 Gene Polymorphisms in Japanese Patients

Umemura¹,

Ôta²,

Hamano³

et al. 2008

The American Journal of Gastroenterology

119

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Objectives: Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well. Methods: Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls. Results: Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64% vs. 42%, odds ratio [OR], 2.48; P = 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR, 0.49; P = 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR, 5.45; P = 0.038 and OR, 12.66; P = 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL; P < 0.001). The +6230G/A polymorphism did not influence sCTLA4 levels in AIP patients. Conclusions: Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

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“…Yet, reports on the association of CTLA-4 with MS have been inconsistent. [32][33][34][35][36][37][38][39][40][41] However confusing the association of CTLA-4 with MS, it is worth considering this gene as a potential contributor to the disease.…”

Section: Ctla-4: a General Marker Of Autoimmunity?mentioning

confidence: 99%