title: 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.
authors.affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center, MA 02215, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Butty
authors.forename: Matt
authors.initials: M
authors.lastname: Roy
authors.forename: Pardis
authors.initials: P
authors.lastname: Sabeti
authors.forename: Whitney
authors.initials: W
authors.lastname: Besse
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D000943:Antigens, Differentiation / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D015810:Linkage Disequilibrium; D008213:Lymphocyte Activation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein