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

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 inter...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-01, Vol.104 (2), p.570-575
Main Authors: Butty, Vincent, Roy, Matt, Sabeti, Pardis, Besse, Whitney, Benoist, Christophe, Mathis, Diane
Format: Article
Language:English
Subjects:
Antigens, CD - genetics
Antigens, Differentiation - genetics
Antigens, Differentiation, T-Lymphocyte - genetics
Asians
Autoimmunity - genetics
Biological Sciences
CD28 Antigens - genetics
Chromosomes, Human, Pair 2 - genetics
CTLA-4 Antigen
Diabetes
Ethnic Groups - genetics
Genes
Genetic linkage
Genetic loci
Genetic Variation
Genetics, Population
Geographic regions
Haplotypes
Humans
Immune system
Inducible T-Cell Co-Stimulator Protein
Linkage Disequilibrium
Lymphocyte Activation
Polymorphism, Single Nucleotide
Population distributions
Population genetics
Promoter Regions, Genetic
Signatures
T cell receptors
T lymphocytes
T-Lymphocytes - immunology
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0610124104