Correspondence

Genomewide Study of Multiple Sclerosis

N Engl J Med 2007; 357:2199-2201November 22, 2007

Article

To the Editor:

Hafler et al. of the International Multiple Sclerosis Genetics Consortium (Aug. 30 issue)1 provide support for the previously tentative association between multiple sclerosis and alleles of the interleukin-2 receptor α gene (IL2RA) and the interleukin-7 receptor α gene (IL7RA). Although the evidence for a limited role of IL7RA in multiple sclerosis is compelling, as noted by Peltonen in the accompanying editorial,2 the data are not definitive. Consistent replication of an effect for IL2RA and IL7RA in various populations would provide stronger evidence of causality.3 In addition, the large effect of the HLA class II region in multiple sclerosis could mask other smaller genetic effects in multiplex families.4,5

The genotyping of 2746 persons from more than 600 Canadian multiplex families, including 1193 with definite multiple sclerosis, showed that genes with small effects can be uncovered in multiplex families, since associations with single-nucleotide polymorphisms (SNPs) in both IL2RA and IL7RA were replicated (Table 1Table 1SNPs in IL2RA and IL7RA Showing a Significant Association with Multiple Sclerosis on the Basis of Transmission Disequilibrium Testing.). However, even with one major locus and potentially two minor loci, much of the genetic basis of multiple sclerosis remains unidentified.

Sreeram V. Ramagopalan, M.A.
Carl Anderson, Ph.D.
Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom

A. Dessa Sadovnick, Ph.D.
University of British Columbia, Vancouver, BC V6T 2B5, Canada

George C. Ebers, M.D.
University of Oxford, Oxford OX3 9DU, United Kingdom
george.ebers@clneuro.ox.ac.uk

5 References

1. 1

   The International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007;357:851-862
   Full Text | Web of Science | Medline

2. 2

   Peltonen L. Old suspects found guilty -- the first genome profile of multiple sclerosis. N Engl J Med 2007;357:927-929
   Full Text | Web of Science | Medline

3. 3

   Chanock SJ, Manolio T, Boehnke M, et al. Replicating genotype-phenotype associations. Nature 2007;447:655-660
   CrossRef | Web of Science | Medline

4. 4

   Howson JM, Barratt BJ, Todd JA, Cordell HJ. Comparison of population- and family-based methods for genetic association analysis in the presence of interacting loci. Genet Epidemiol 2005;29:51-67
   CrossRef | Web of Science | Medline

5. 5

   Li M, Boehnke M, Abecasis GR. Efficient study designs for test of genetic association using sibship data and unrelated cases and controls. Am J Hum Genet 2006;78:778-792
   CrossRef | Web of Science | Medline

To the Editor:

The genomewide association study of multiple sclerosis showed two SNPs in the IL2RA gene that were significantly associated with the disease. We reported a SNP (rs1570538) in the IL2RA gene that was associated with multiple sclerosis in a Spanish population.1 The article by Hafler et al. suggests that our finding may represent a chance observation unrelated to multiple sclerosis, although no reason for that suggestion is given. We note that none of the IL2RA SNPs associated with multiple sclerosis corresponded to SNPs in the same locus that were reported to be associated with type 1 diabetes.2 These results reflect a complex situation. Functional studies will be required to uncover the causal SNPs and to determine what effects they have on the IL2RA protein and its role in multiple sclerosis.3

Fuencisla Matesanz, Ph.D.
Instituto de Parasitología y Biomedicina López Neyra, 18100 Granada, Spain

Óscar Fernández, M.D., Ph.D.
Hospital Regional Universitario Carlos Haya, 29010 Málaga, Spain

Antonio Alcina, M.Sc., Ph.D.
Instituto de Parasitología y Biomedicina López Neyra, 18100 Granada, Spain
pulgoso@ipb.csic.es

3 References

1. 1

   Matesanz F, Caro-Maldonado A, Fedetz M, et al. IL2RA/CD25 polymorphisms contribute to multiple sclerosis susceptibility. J Neurol 2007;254:682-684
   CrossRef | Web of Science | Medline

2. 2

   Lowe CE, Cooper JD, Brusko T, et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 2007;39:1074-1082
   CrossRef | Web of Science | Medline

3. 3

   Matesanz F, Fedetz M, Alcina A. IL2 biology and polymorphisms in multifactorial conditions. In: Vandenbroeck K, ed. Cytokine gene polymorphisms in multifactorial conditions. London: Taylor and Francis, 2006:109-19.
   

To the Editor:

Peltonen makes a giant leap of faith in extrapolating the findings of Hafler et al. to a T-cell–mediated autoimmune mechanism in multiple sclerosis. Hafler et al. found an extremely modest risk conferred by IL2RA and IL7RA genes. The association of the HLA class II locus should not be interpreted as an essential indicator of autoimmunity; narcolepsy is also associated with this locus. The association between multiple sclerosis and the HLA locus may indicate only the genetic vulnerability of patients in whom the disease develops after exposure to environmental triggers. For example, the concordance rate of multiple sclerosis in monozygotic twins is modest, and the genetic risk can be attenuated by increasing exposure to sunlight in childhood.1

Abhijit Chaudhuri, M.D., Ph.D.
Queen's Hospital, London RM7 0AG, United Kingdom
chaudhuria@gmail.com

Peter O. Behan, M.D., D.Sc.
University of Glasgow, Glasgow G51 4TF, Scotland

1 References

1. 1

   Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007;69:381-388
   CrossRef | Web of Science | Medline

Author/Editor Response

Replication is a critical component of all genetics studies, and the work by Ramagopalan et al. substantiates a role for IL2RA and IL7RA in multiple sclerosis. We agree that much of the genetic basis of multiple sclerosis remains unidentified. In our article, we stated that each of the alleles that were identified in our genomewide scan explained only “a small proportion (less than 0.2%) of the variance in the risk of the development of multiple sclerosis.”

In their study, Matesanz et al. typed four variants of IL2RA in a cohort of 346 case subjects and 418 control subjects. One of these variants (rs1570538) reached borderline significance, but the authors made no correction for multiple testing. Even if one of our IL2RA-associated variants, rs12722489, had been found in the study by Matesanz et al., the relatively small number of case subjects and control subjects they studied means that they would have had only a one-in-three chance of showing an association between the SNP and multiple sclerosis at the significance level of 5%. Given the low statistical power of their study and the virtual absence of any correlation between rs1570538 and rs12722489 (r²=0.1), we felt that we were justified in stating that their observation “may represent an unrelated chance observation.” We believe that any concordance between the results reported by Matesanz et al. and our association between rs12722489 and multiple sclerosis is probably a coincidence.

The published literature concerning the genetics of multiple sclerosis is replete with studies based on fewer than 500 case subjects and 500 control subjects. In hindsight, it is now clear that these studies were underpowered. As a result, many promising candidate loci may have been wrongly rejected on the basis of such studies, whereas other loci will ultimately prove to be genuine, even though any apparently positive associations shown in these studies are unrelated and probably represent no more than sampling variance.

David A. Hafler, M.D.
Brigham and Women's Hospital, Boston, MA 02115
dhafler@rics.bwh.harvard.edu

Alastair Compston, F.Med.Sci., Ph.D.
University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, United Kingdom

Stephen L. Hauser, M.D.
University of California at San Francisco, San Francisco, CA 94122

for the International Multiple Sclerosis Genetics Consortium

Citing Articles (15)

Citing Articles

1. 1

   Marie-Claude Babron, Hervé Perdry, Adam E Handel, Sreeram V Ramagopalan, Vincent Damotte, Bertrand Fontaine, Bertram Müller-Myhsok, George C Ebers, Françoise Clerget-Darpoux. (2011) Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis. European Journal of Human Genetics
   CrossRef

2. 2

   Abolghasem Kollaee, Majid Ghaffarpor, Hosein Pourmahmoudian, Majid Shahbazi, Mahdi Zamani. (2011) Investigation of CD24 and Its Expression in Iranian Relapsing-Remitting Multiple Sclerosis. International Journal of Neuroscience 121:12, 684-690
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3. 3

   Edwin Hoe, Fiona McKay, Steven Schibeci, Rob Heard, Graeme Stewart, David Booth. (2010) Interleukin 7 Receptor Alpha Chain Haplotypes Vary in Their Influence on Multiple Sclerosis Susceptibility and Response to Interferon Beta. Journal of Interferon & Cytokine Research 30:5, 291-298
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4. 4

   Raija L. P. Lindberg, Francine Hoffmann, Matthias Mehling, Jens Kuhle, Ludwig Kappos. (2010) Altered expression of miR-17-5p in CD4 ⁺ lymphocytes of relapsing-remitting multiple sclerosis patients. European Journal of Immunology 40:3, 888-898
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5. 5

   Adam E. Handel, Lahiru Handunnetthi, George C. Ebers, Sreeram V. Ramagopalan. (2009) Type 1 diabetes mellitus and multiple sclerosis: common etiological features. Nature Reviews Endocrinology 5:12, 655-664
   CrossRef

6. 6

   Philip L De Jager, Xiaoming Jia, Joanne Wang, Paul I W de Bakker, Linda Ottoboni, Neelum T Aggarwal, Laura Piccio, Soumya Raychaudhuri, Dong Tran, Cristin Aubin, Rebeccah Briskin, Susan Romano, Sergio E Baranzini, Jacob L McCauley, Margaret A Pericak-Vance, Jonathan L Haines, Rachel A Gibson, Yvonne Naeglin, Bernard Uitdehaag, Paul M Matthews, Ludwig Kappos, Chris Polman, Wendy L McArdle, David P Strachan, Denis Evans, Anne H Cross, Mark J Daly, Alastair Compston, Stephen J Sawcer, Howard L Weiner, Stephen L Hauser, David A Hafler, Jorge R Oksenberg. (2009) Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genetics 41:7, 776-782
   CrossRef

7. 7

   Devindri Perera, Jim Stankovich, Helmut Butzkueven, Bruce V. Taylor, Simon J. Foote, Trevor J. Kilpatrick, Justin P. Rubio. (2009) Fine mapping of multiple sclerosis susceptibility genes provides evidence of allelic heterogeneity at the IL2RA locus. Journal of Neuroimmunology 211:1-2, 105-109
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8. 8

   Nicolas Couturier, Pierre-Antoine Gourraud, Isabelle Cournu-Rebeix, Claire Gout, Florence Bucciarelli, Gilles Edan, Marie-Claude Babron, Françoise Clerget-Darpoux, Michel Clanet, Bertrand Fontaine, David Brassat. (2009) IFIH1-GCA-KCNH7 locus is not associated with genetic susceptibility to multiple sclerosis in French patients. European Journal of Human Genetics 17:6, 844-847
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9. 9

   P. L. De Jager, C. Baecher-Allan, L. M. Maier, A. T. Arthur, L. Ottoboni, L. Barcellos, J. L. McCauley, S. Sawcer, A. Goris, J. Saarela, R. Yelensky, A. Price, V. Leppa, N. Patterson, P. I. W. de Bakker, D. Tran, C. Aubin, S. Pobywajlo, E. Rossin, X. Hu, C. W. Ashley, E. Choy, J. D. Rioux, M. A. Pericak-Vance, A. Ivinson, D. R. Booth, G. J. Stewart, A. Palotie, L. Peltonen, B. Dubois, J. L. Haines, H. L. Weiner, A. Compston, S. L. Hauser, M. J. Daly, D. Reich, J. R. Oksenberg, D. A. Hafler. (2009) The role of the CD58 locus in multiple sclerosis. Proceedings of the National Academy of Sciences 106:13, 5264-5269
   CrossRef

10. 10

    S. P. Kallio, E. Jakkula, S. Purcell, M. Suvela, K. Koivisto, P. J. Tienari, I. Elovaara, T. Pirttila, M. Reunanen, D. Bronnikov, M. Viander, S. Meri, J. Hillert, F. Lundmark, H. F. Harbo, A. R. Lorentzen, P. L. De Jager, M. J. Daly, D. A. Hafler, A. Palotie, L. Peltonen, J. Saarela. (2009) Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Human Molecular Genetics 18:9, 1670-1683
    CrossRef

11. 11

    J P Rubio, J Stankovich, J Field, N Tubridy, M Marriott, C Chapman, M Bahlo, D Perera, L J Johnson, B D Tait, M D Varney, T P Speed, B V Taylor, S J Foote, H Butzkueven, T J Kilpatrick. (2008) Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians. Genes and Immunity 9:7, 624-630
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12. 12

    I Cournu-Rebeix, E Génin, E Leray, M-C Babron, J Cohen, C Gout, M Alizadeh, H Perdry, G Semana, D Brassat, F Clerget-Darpoux, J Yaouanq, G Edan, M Rosenheim, B Fontaine. (2008) HLA-DRB1*15 allele influences the later course of relapsing remitting multiple sclerosis. Genes and Immunity 9:6, 570-574
    CrossRef

13. 13

    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
    CrossRef

14. 14

    Jorge R. Oksenberg, Sergio E. Baranzini, Stephen Sawcer, Stephen L. Hauser. (2008) The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nature Reviews Genetics 9:7, 516-526
    CrossRef

15. 15

    F Weber, B Fontaine, I Cournu-Rebeix, A Kroner, M Knop, S Lutz, F Müller-Sarnowski, M Uhr, T Bettecken, M Kohli, S Ripke, M Ising, P Rieckmann, D Brassat, G Semana, M-C Babron, S Mrejen, C Gout, O Lyon-Caen, J Yaouanq, G Edan, M Clanet, F Holsboer, F Clerget-Darpoux, B Müller-Myhsok. (2008) IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes and Immunity 9:3, 259-263
    CrossRef