Correspondence

IL7RA Polymorphisms and Susceptibility to Multiple Sclerosis

N Engl J Med 2008; 358:753-754February 14, 2008

Article

To the Editor:

Two independent, well-powered studies have recently identified the interleukin-7 receptor α (IL7RA) gene as a susceptibility gene for multiple sclerosis,1,2 thus extending and confirming earlier observations.3,4 A functional, nonsynonymous single-nucleotide polymorphism (SNP), rs6897932, located in the alternatively spliced sixth exon of the gene, was highlighted as the susceptibility-modifying polymorphism, with the C allele increasing the risk of disease (odds ratio, approximately 1.2).1,2

We genotyped nine haplotype-tagging SNPs in IL7RA in two independent case–control collections from Olmsted County, Minnesota, and Belfast, Northern Ireland, neither of which, to our knowledge, has previously been tested for IL7RA (Table 1Table 1Allele Count and Frequency of IL7RA SNPs in Patients with Multiple Sclerosis and Controls.). Clinical and demographic data for both collections have been described elsewhere.5 Analysis of the Olmsted County genotype data revealed an association between multiple sclerosis and the rs6897932*C allele (P=0.00504; 10,000-permutation–corrected P=0.035; odds ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.0). However, this association was not found in the Belfast collection. CC genotype counts (vs. T carriage) were increased in patients with multiple sclerosis, as compared with controls, in Olmsted County (P=0.0049; odds ratio, 1.6; 95% CI, 1.1 to 2.3).

Haplotype analysis showed that in the Olmsted County patients with multiple sclerosis, the frequency of the GCGTACAAT haplotype was decreased (22%, vs. 30% in controls; uncorrected P=0.0023; 10,000-permutation–corrected P=0.02) and that of the GCGCACAAT haplotype was increased (21%, vs. 13% in controls; uncorrected P=0.0003; 10,000-permutation–corrected P=0.0035). In contrast, no such differences were observed in the Belfast collection.

The association between rs6897932 and multiple sclerosis in the Olmsted County collection appeared to be much stronger than anticipated on the basis of the recent studies1,2 and was therefore detectable in a collection that in principle was underpowered. The absence of an association in the Belfast collection may reflect heterogeneity of the population or lack of statistical power.

Catherine O'Doherty, Ph.D., M.Pharm.
Queen's University of Belfast, Belfast BT9 7BL, United Kingdom

Orhun Kantarci, M.D.
Mayo Clinic, Rochester, MN 55905

Koen Vandenbroeck, Ph.D., M.Sc.
Queen's University of Belfast, Belfast BT9 7BL, United Kingdom
k.vandenbroeck@qub.ac.uk

Supported by a grant from the Multiple Sclerosis Society of Ireland.

Dr. Vandenbroeck reports receiving grant support from Biogen Idec and lecture fees from Serono. No other potential conflict of interest relevant to this letter was reported.

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Citing Articles (12)

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   K Vandenbroeck, J Alvarez, B Swaminathan, I Alloza, F Matesanz, E Urcelay, M Comabella, A Alcina, M Fedetz, M A Ortiz, G Izquierdo, O Fernandez, N Rodriguez-Ezpeleta, C Matute, S Caillier, R Arroyo, X Montalban, J R Oksenberg, A Antigüedad, A Aransay. (2012) A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis. Genes and Immunity 13:1, 21-28
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   Koen Vandenbroeck. (2011) Cytokine Gene Polymorphisms and Human Autoimmune Disease in the Era of Genome-Wide Association Studies. Journal of Interferon & Cytokine Research111222120228007
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   Ruijie Zhang, Lian Duan, Yongshuai Jiang, Xuehong Zhang, Peng Sun, Jin Li, Mingming Zhang, Guoping Tang, Xing Wang, Xia Li. (2011) Association between the IL7R T244I polymorphism and multiple sclerosis: a meta-analysis. Molecular Biology Reports 38:8, 5079-5084
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   Moones Heidari, Mehrdad Behmanesh, Mohammad-Ali Sahraian. (2011) Variation in SNPs of the IL7Ra Gene is Associated with Multiple Sclerosis in the Iranian Population. Immunological Investigations 40:3, 279-289
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   Sabine Hoffjan, Denis A. Akkad. (2010) The genetics of multiple sclerosis: An update 2010. Molecular and Cellular Probes 24:5, 237-243
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   C. O'Doherty, I. Alloza, M. Rooney, K. Vandenbroeck. (2009) IL7RA polymorphisms and chronic inflammatory arthropathies. Tissue Antigens 74:5, 429-431
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    D.A. Akkad, S. Hoffjan, E. Petrasch-Parwez, J. Beygo, R. Gold, J.T. Epplen. (2009) Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. Journal of Autoimmunity 32:2, 110-115
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    A. Alcina, M. Fedetz, D. Ndagire, O. Fernndez, L. Leyva, M. Guerrero, C. Arnal, C. Delgado, F. Matesanz. (2008) The T244I variant of the interleukin-7 receptor-alpha gene and multiple sclerosis. Tissue Antigens 72:2, 158-161
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