title: Interleukin 7 receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta.
abstract: Interleukin 7 receptor alpha chain (IL-7Ralpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Ralpha, and therefore reduced interference with receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Ralpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Ralpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend only), and in CD4 + CD45RO + and CD4 + CD45RA + cells. In PBMCs, IL-7Ralpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P < 0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7Ralpha by IFN-beta may contribute to the genetic association of IL-7Ralpha with MS.
authors.affiliation: Westmead Millennium Institute, University of Sydney , Australia.
authors.forename: Edwin
authors.initials: E
authors.lastname: Hoe
authors.forename: Fiona
authors.initials: F
authors.lastname: McKay
authors.forename: Steven
authors.initials: S
authors.lastname: Schibeci
authors.forename: Rob
authors.initials: R
authors.lastname: Heard
authors.forename: Graeme
authors.initials: G
authors.lastname: Stewart
authors.forename: David
authors.initials: D
authors.lastname: Booth
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002469:Cell Separation; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D007114:Immunization; D016899:Interferon-beta / Q000494:pharmacology; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D015201:Meta-Analysis as Topic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*
chemical_list: D053699:Interleukin-7 Receptor alpha Subunit; D016899:Interferon-beta