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Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

Genes & Immunity volume 6, pages 145–152 (2005)Cite this article

Abstract

Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this two-stage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (P<0.08) between patients and controls. After additional genotyping in stage two, two genes—each containing at least three significantly (P<0.05) associated SNPs—conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis—and, by extension, derangement of immune homeostasis—influence the risk of MS.

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Acknowledgements

This study was supported by grants from the European Commission, the Swedish Medical Research Council, the Swedish Association of Neurologically Disabled, the Swedish Society of Medicine, the Swedish Brain Foundation, the Lars Hierta Foundation, the Swedish Foundation for Strategic Research, and Karolinska Institutet. We thank Nancy Pedersen of the Swedish Twin Registry and all the patients and volunteers who participated in the study.

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Author notes

  1. K Duvefelt and F Svensson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Sciences, Section for Genetics and Bioinformatics, AstraZeneca R&D Södertälje, Södertälje, Sweden

    Z Zhang, F Svensson, H Salter, T Emahazion, D Hellgren, G Falk & M Anvret

  2. Neurotec Department, Division of Neurology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden

    K Duvefelt, F Svensson, T Masterman & J Hillert

  3. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden

    G Jonasdottir

  4. Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden

    T Olsson

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  1. Z Zhang
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Correspondence to F Svensson.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene).

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Zhang, Z., Duvefelt, K., Svensson, F. et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 6, 145–152 (2005). https://doi.org/10.1038/sj.gene.6364171

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