Abstract
We have investigated the association of multiple sclerosis (MS) with polymorphisms in the IL4R gene in 332 single-case MS families. IL4R encodes a subunit of the interleukin-4 receptor, a molecule important for T-cell development and differentiation, and is a gene shown to be associated with immune-related diseases such as asthma and type I diabetes. By genotyping two promoter and eight coding IL4R SNPs and identifying haplotypes (complex alleles) in the MS families, stratified for HLA genotype, we have observed evidence of the association of the IL4R gene to MS. In particular, we have identified a specific susceptibility haplotype, and observe that the risk is conferred primarily to individuals not carrying the high MS-risk HLA DR2 (DRB1*1501-DQB1*0602) haplotype (nominal P=0.009). These findings suggest a potentially important role for the IL4R gene in predisposition to MS, and provide further evidence of its relevance as a candidate gene for immune-related diseases.
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References
Compston A, Coles A . Multiple sclerosis. Lancet 2002; 359: 1221–1231.
Lublin FD, Reingold SC . Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46: 907–911.
Oksenberg JR, Baranzini SE, Barcellos LF, Hauser SL . Multiple sclerosis: genomic rewards. J Neuroimmunol 2001; 113: 171–184.
Hauser S, Goodkin D . Multiple Sclerosis and other demyelinating diseases. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL (eds). Harrison's Principles of Internal Medicine 15 edn. McGraw-Hill: New York, 2001, pp 2452–2461.
Chataway J, Feakes R, Coraddu F et al. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain 1998; 121: 1869.
Barcellos LF, Oksenberg JR, Green AJ et al. Genetic basis for clinical expression in multiple sclerosis. Brain 2002; 125: 150–158.
Haines J, Terwedow H, Burgess K et al. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet 1998; 7: 1229–1234.
Ligers A, Dyment DA, Willer CJ et al. Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis. Am J Hum Genet 2001; 69: 900–903.
Kantarci OH, de Andrade M, Weinshenker BG . Identifying disease modifying genes in multiple sclerosis. J Neuroimmunol 2002; 123: 144–159.
Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE . The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 1999; 17: 701–738.
Hulshof S, Montagne L, De Groot CJ, Van Der Valk P . Cellular localization and expression patterns of interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions. Glia 2002; 38: 24–35.
Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM . Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today 2000; 21: 60–64.
Ober C, Leavitt SA, Tsalenko A et al. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 2000; 66: 517–526.
Hackstein H, Hofmann H, Bohnert A, Bein G . Definition of human interleukin-4 receptor alpha chain haplotypes and allelic association with atopy markers. Hum Immunol 1999; 60: 1119–1127.
Bugawan TL, Mirel DB, Valdes AM, Panelo A, Pozzilli P, Erlich HA . Association and interaction of the IL4R, IL4, and IL13 loci with type 1 diabetes among Filipinos. Am J Hum Genet 2003; 72: 1505–1514.
Mirel DB, Valdes AM, Lazzeroni LC, Reynolds RL, Erlich HA, Noble JA . Association of IL4R haplotypes with type 1 diabetes. Diabetes 2002; 51: 3336–3341.
He B, Xu C, Yang B, Landtblom A-M, Fredrikson S, Hillert J . Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis. J Neuroimmunol 1998; 86: 13–19.
Hackstein H, Bitsch A, Bohnert A et al. Analysis of interleukin-4 receptor alpha chain variants in multiple sclerosis. J Neuroimmunol 2001; 113: 240–248.
Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.
Barcellos LF, Oksenberg JR, Begovich AB et al. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 2003; 72: 710–716.
Higuchi R, Fockler C, Dollinger G, Watson R . Kinetic PCR analysis: real-time monitoring of DNA amplification reactions. Biotechnology (NY) 1993; 11: 1026–1030.
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58: 1347–1363.
Kruglyak L, Lander ES . Faster multipoint linkage analysis using Fourier transforms. J Comput Biol 1998; 5: 1–7.
Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.
Hackstein H, Hecker M, Kruse S et al. A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics 2001; 53: 264–269.
Acknowledgements
We thank Alina Kim for technical assistance and our colleagues for helpful discussions. This work is funded in part by NIH Grants R01 AI29042-09A1 to HAE and NMSS RG2901 to JRO.
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Mirel, D., Barcellos, L., Wang, J. et al. Analysis of IL4R haplotypes in predisposition to multiple sclerosis. Genes Immun 5, 138–141 (2004). https://doi.org/10.1038/sj.gene.6364048
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DOI: https://doi.org/10.1038/sj.gene.6364048
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