Technical Note: Linkage Disequilibrium and Disease-Associated CTLA4 Gene Polymorphisms

Abstract

CTLA4 and CD28 are important regulators of T lymphocyte activation. Gene region 2q33 carrying genes for both CTLA4 and CD28 has been shown to be linked to many autoimmune diseases. Disease associations with particular CTLA4 gene polymorphisms have been reported. Recently, first lines of evidence emerged for functional effects of CTLA4 gene polymorphisms. Two independent studies reported a reduced inhibitory function of CTLA4 in individuals with certain CTLA4 genotypes: those with a high number of microsatellite repeats in one study and those with allele +49*G in exon 1 in the other one. We analyzed the strength of linkage disequilibrium between the three known CTLA4 polymorphisms among 577 independent chromosomes. Our results show that the polymorphisms previously suggested to be the functional risk factors nearly always occur together in a very frequent haplotype. Due to this strong linkage disequilibrium, we conclude that the previous reports studying merely a single polymorphism could not distinguish which variation actually caused the functional difference. Hence, either mutagenesis approaches or studies with data on all linked polymorphisms are still needed to determine the genuine functional risk polymorphism in this gene region.

Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) gene polymorphism and susceptibility to non‐Hodgkin's lymphoma

“…Alleles with long repeat regions have been associated with Grave's disease, myasthenia gravis, and multiple myeloma and have been correlated with a decrease in the CTLA-4 inhibitory function in myasthenia gravis [6,19,20]. In agreement with previous reports on allelic frequencies of the CTLA-4 (AT) n polymorphism in Caucasian populations [12,21], we found a high frequency of the short allele (AT) 8 in NHL patients and controls. However, no association of the CTLA-4 microsatellite polymorphism with NHL was detected.…”

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

“…We found that the presence of the GG genotype resulted in less increase in T-cell proliferation upon blocking CTLA-4 when compared to the AA genotype. Similarly, other investigators have examined the effects of the A and G alleles of the CTLA-4 A/G 49 SNP on the inhibitory function of CTLA-4. [44][45][46] The GG genotype was found to be associated with reduced inhibitory function of CTLA-4 on T-cell proliferation after stimulation with an allogeneic cell line, and with decreased CTLA-4 surface expression.…”

“…Therefore, the A/G 49 SNP can be used as a surrogate marker until the causative polymorphism is identified. Indeed, preliminary data in myasthenia gravis showed that the (AT)n microsatellite at the 3 0 UTR of the CTLA-4 gene influenced the half-life of the CTLA-4 mRNA, 48,49 and contributed to decreased mRNA stability. 50 This could provide an attractive explanation for the association between the short alleles of the (AT)n microsatellite and AITD, as well as other autoimmune diseases.…”

Genetic association of coeliac disease susceptibility to polymorphisms in the ICOS gene on chromosome 2q33

“…3 However, there is no actual evidence that the CTLA4 þ 49 SNP as such were the genuine susceptibility factor. Owing to strong linkage disequilibrium (LD) in the region, 4 the identification of the primary susceptibility polymorphism may not be an easy task. Also, similar to the HLA loci, there can be multiple alleles or genes playing a role.…”