Signatures of strong population differentiation shape extended haplotypes across the human CD28 , CTLA4 , and ICOS costimulatory genes

Abstract

The three members of the costimulatory receptor family, CD28, CTLA-4, and ICOS, have complementary effects on T cell activation, and their balance controls the overall outcome of immune and autoimmune responses. They are encoded in a short genomic interval, and overall activity may result from interplay between allelic variants at each locus. With multiethnic DNA panels that represent a wide spectrum of human populations, we demonstrate long-range linkage disequilibrium among the three genes. A large fraction of the variation found in the locus can be explained by the presence of extended haplotypes encompassing variants at CD28, CTLA4, and the ICOS promoter. There are unusual differences in the distribution of some variants and haplotypes between geographic regions. The differences may reflect demographic events and/or the adaptation to diverse environmental and microbial challenges encountered in the course of human migrations and will be important to consider when interpreting association to immune/ autoimmune responsiveness.autoimmunity ͉ linkage disequilibrium ͉ T cell costimulation

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

“…Our finding of LD between markers in the CTLA4-ICOSe1 and ICOSe2-5 haploblocks supports this. The structure and frequency of haplotypes in the current study are also in accordance with those in the European populations studied by Butty et al 27 The haplotype identified as most common in those European populations is part of our CTLA4-ICOSe1 risk haplotype group 2. Both our risk haplotype groups 2 and 4 carry the allele most commonly associated with CD, rs231775*A (CTLA4 þ 49*A) (Table 5a).…”

“…25,29 A recent study by Butty et al 27 of LD patterns and haplotypes in the CD28-CTLA4-ICOS gene region in a number of populations revealed extended haplotypes covering the whole region. Our finding of LD between markers in the CTLA4-ICOSe1 and ICOSe2-5 haploblocks supports this.…”

“…There have been numerous reports of linkage or association of the nearby CTLA4 and ICOS genes with several diseases, although most of the earlier studies have focused their analysis on only a few CTLA4 polymorphisms. There is a recombination hot spot in the first intron of ICOS, dividing the gene into two LD blocks, 27 referred to as CTLA4-ICOSe1 and ICOSe2-5 in Figure 1. This strong LD makes it challenging to distinguish between association with CTLA4 and the promoter of ICOS.…”

Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy

“…The three members of the costimulatory receptor family, CD28, CTLA4, and ICOS, encoded in a short genomic interval, have complementary effects on T-cell activation and their balance has been shown to control the overall outcome of immune responses. 35 Butty et al 35 have shown that functional variation in the CD28/CTLA4/ICOS region may not be due to polymorphism in a single gene, but to the combination of genetic variants at the three loci. Thus, SNPs in other costimulatory receptors may also be associated with DCM and should be systematically investigated in future studies.…”

Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients

“…CTLA-4, a receptor structurally homologous to CD28, acts as a negative regulator of T cell responses by interacting with B7 molecules on antigen presenting cells; in contrast, a costimulatory signal is evoked by CD28-B7 interaction (Ling et al 2001, Butty et al 2007). Antibody-mediated blockage of CTLA-4 in vivo has been demonstrated to upregulate the immune response in murine models of infection, autoimmune disease, tumour immunity, allergy and vaccination , Thio et al 2004).…”