title: Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource.
abstract: Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases. However, identifying causal genes within an associated region remains a major challenge. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Calliope A
authors.initials: CA
authors.lastname: Dendrou
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Erik
authors.initials: E
authors.lastname: Fung
authors.forename: Jennie H M
authors.initials: JH
authors.lastname: Yang
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Gillian
authors.initials: G
authors.lastname: Coleman
authors.forename: Matthew
authors.initials: M
authors.lastname: Himsworth
authors.forename: Matthew
authors.initials: M
authors.lastname: Hardy
authors.forename: Oliver
authors.initials: O
authors.lastname: Burren
authors.forename: Barry
authors.initials: B
authors.lastname: Healy
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Kerstin
authors.initials: K
authors.lastname: Koch
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: John R
authors.initials: JR
authors.lastname: Bradley
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D018070:Biological Specimen Banks; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D013601:T-Lymphocytes / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D055815:Young Adult
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit
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