Lack of association between sCTLA-4 levels in human plasma and common CTLA-4 polymorphisms

Abstract

Background: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important downregulatory molecule expressed on both T and B lymphocytes. Numerous population genetics studies have documented significant associations between autoimmune diseases and single nucleotide polymorphisms (SNPs) within and around the CTLA-4 region of chromosome 2 in man. Furthermore, circulating levels of a soluble form of CTLA-4 (sCTLA-4) have been reported in a variety of autoimmune mediated diseases. Despite these findings, the relationship between levels of sCTLA-4 protein, mRNA transcript levels, and SNPs within the CTLA-4 region have not been clearly defined. In order to further clarify this relationship, we have tested four different SNPs within the CTLA-4 region among subjects whom are negative (n = 53) versus positive (n = 28) for sCTLA-4.

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

“…Thus, our data do not support a relationship between these tested SNPs and circulating levels of CTLA-4 in the presence or absence of autoimmune disease. These results are in agreement with the study of Berry et al (2008), who found no statistically significant differences in observed versus expected genotypic frequencies for these SNPs when comparing positive versus negative blood levels of sCTLA-4.…”

“…It is thus not surprising that genetic variation within this region is implicated in susceptibility to autoimmune disease (Berry et al, 2008). The association of autoimmune diseases with the CTLA-4 locus could represent the effects of any of these three genes alone or in combination due to linkage disequilibrium.…”

“…In the Ueda et al (2003), model, the CT60-G susceptibility allele appears to produce lower relative amounts of the sCTLA-4 mRNA; thus, one would expect that subjects at risk for autoimmune disease to have reduced levels of sCTLA-4 protein. It seems paradoxical given that lower levels of CTLA-4 message are present in susceptible individuals whereas higher levels of sCTLA-4 protein are observed in plasma of individuals with autoimmune disease (Berry et al, 2008). Possible explanations for the appearance of this discrepancy may include the possibility that there is no direct relationship between message levels at the cellular level and circulating protein in plasma.…”

“…For example, elevated circulating CTLA-4 levels may simply be due to increased half-life and/or decreased turnover of protein despite increased levels of synthesis. Also, it is possible that lower levels of CTLA-4 message reflect a feedback regulatory loop in which mRNA levels are reduced in the face of higher levels of CTLA-4 protein (Berry et al, 2008).…”

Soluble CTLA-4 receptor an immunological marker of Graves' disease and severity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymorphisms

“…We found a significant correlation of the two SNPs in 3 0 UTR of the CTLA-4 gene, which were shown to be in strong linkage disequilibrium (32) (20,25) did not observe any relation between CT60 polymorphism and serum sCTLA-4 level. We did not report any significant correlation of other CTLA-4 gene polymorphisms studied with sCTLA-4 level in serum; however, we noted that promoter polymorphism (g.319COT) tended to be associated with higher sCTLA-4 levels.…”