Gregory, S. G., Schmidt, S., Seth, P., Oksenberg, J. R., Hart, J., Prokop, A. et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. 39, 1083-1091

Center for Human Genetics, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature Genetics (Impact Factor: 29.35). 10/2007; 39(9):1083-91. DOI: 10.1038/ng2103
Source: PubMed


Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.

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    • "Recent genetic studies strongly implicate the IL-7Rα-related immune response pathway in the etiology of MS (Gregory et al., 2007). The impact of IL-7/IL-7Rα signaling on CD4 + T cells (Kreft et al., 2012a), Treg cells (Haas et al., 2011), and CD8 + T cells (Kreft et al., 2012b) in MS has been reported to demonstrate that this pathway may subsequently enhance the pathogenicity of these immune cells. "
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    ABSTRACT: Decreased NK cell numbers and impairment of NK cell function are reported in patients with multiple sclerosis (MS). Interleukin-7 (IL-7) is a member of the common gamma-chain (γc) cytokine superfamily that has well documented roles in lymphocyte development and homeostasis. The interleukin-7 receptor α chain (IL-7Rα) gene was identified as a top non-major histocompatibility complex-linked risk locus for MS. The objective of this study was to test biological function of IL-7/IL-7Rα on NK cells in MS patients. We observed markedly lower IL-7 levels in MS sera, and relatively higher IL-7Rα expression in NK cells of MS. Upon IL-7 stimulation, IL-7Rα on NK cells from MS patients was significantly down-regulated compared with healthy controls (HC). IL-7 induced a higher increase of IFN-γ production in CD56bright NK cells and a pronounced enhancement of cytotoxicity in NK cells from MS. IL-7 does not impact the proliferation of NK cells differently in MS and HC. In contrast, IL-7 promotes a higher survival of CD56bright NK cells in MS and inhibits their apoptosis by increasing Bcl-2 expression, but has no effect on CD56dim NK cell survival in MS. In conclusion, MS patients have lower serum IL-7 and a higher membrane IL-7Rα expression on CD56bright NK cells. The skew at the IL-7 and IL-7Rα level influences functional responsiveness of NK cells in MS.
    Full-text · Article · Aug 2014 · Journal of Neuroimmunology
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    • "Following the discovery of MHC in MS, literally hundreds of candidate-gene based association studies investigating hundreds of genes were published with contradictory results. Among these, IL7RA (encoding the interleukin receptor 7A) was initially assessed and reported as a putative MS risk gene using a candidate-gene approach (7–9) and still shows convincing evidence for association with MS today (6, 10). However, it was only since the first applications of the genome-wide association study (GWAS) approach that the majority of today’s established genetic association findings were uncovered: since 2007 several MS GWAS and follow-up studies have been published each expanding the number of (mostly) genuine risk loci. "
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    ABSTRACT: Multiple sclerosis (MS) is the most common auto-inflammatory disease of the central nervous system, affecting more than 2 million individuals worldwide. It is a genetically complex disease, in which a substantial part of a person's liability to develop MS is caused by a combination of multiple genetic and non-genetic (e.g., environmental) risk factors. Increasing this complexity, many of the involved risk factors likely interact in an intricate and hitherto ill-defined fashion. Despite these complexities, and owing greatly to the advent and application of large-scale genome-wide association studies, our understanding of the genetic factors underlying MS etiology has begun to gain unprecedented momentum. In this perspective, I will summarize some recent advances and outline future challenges in MS genetics research.
    Full-text · Article · Jul 2014 · Frontiers in Neurology
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    • "IRF8 has been associated with regulating innate immunity, with B cell development, and with the differentiation of CD8+ T cells [24]. IL7 is important to many immune functions, including T cell differentiation and maintenance, and the IL7R polymorphism confers a functional change; specifically, it leads to an increase in the soluble (versus membrane-bound) form of the IL7R α chain [25]. Finally, the CD6 gene product is involved in continuing the activation of T cells; CD4+ T cell proliferation is reduced in healthy people with two copies of the risk allele [26]. "
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    ABSTRACT: The anatomic location of subsequent relapses in early multiple sclerosis (MS) appears to be predicted by the first attack location. We sought to determine if genetic polymorphisms associated with MS susceptibility are associated with attack location. 17 genome-wide association study-identified MS susceptibility polymorphisms were genotyped in 503 white, non-Hispanic patients seen within a year of MS onset. Their association with the CNS location of the first two MS attacks was assessed in multivariate repeated measures analyses (generalized estimating equations with robust standard errors). The IL12A polymorphism was independently associated with increased odds of attacks involving the spinal cord (OR = 1.52, 95% CI 1.11, 2.07, p = 0.009), as was the IRF8 polymorphism (OR = 2.40, 95% CI [1.04, 5.50], p = 0.040). The IL7R polymorphism was associated with reduced odds of attacks involving the brainstem/cerebellum (OR = 0.46, 95% CI 0.22, 0.97, p = 0.041), as were the TNFRSF1A and IL12A polymorphisms. The CD6 polymorphism conferred reduced odds of optic neuritis as an attack location (OR = 0.69, 95% CI [0.49, 0.97], p = 0.034). Several other genes showed trends for association with attack location. Some of the MS susceptibility genes may be associated with MS attack location. The IL12A polymorphism is of particular interest given that interferon beta therapy appears to influence IL12 levels. These findings may lead to improved understanding of MS pathogenesis and treatment.
    Full-text · Article · Oct 2013 · PLoS ONE
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