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Crohn’s associated NOD2 gene variants are not involved in determining susceptibility to multiple sclerosis
  1. S Sawcer,
  2. M Maranian,
  3. A Hensiek,
  4. R Roxburgh,
  5. J Gray,
  6. A Compston
  1. University of Cambridge Neurology unit, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK
  1. Correspondence to:
 Professor Alastair Compston; 

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Autoimmune diseases, such as multiple sclerosis and Crohn’s disease, are believed to result from the effects of environmental agents acting on genetically susceptible individuals. Evidence from segregation analysis and systematic whole genome linkage studies indicates that the nature of this susceptibility is complex, involving several genes which each individually confer only modest excess risk. Recurrence risk analysis in the relatives of affected individuals1 together with the comparison of whole genome linkage studies across these diseases2 shows that there are likely to be both genes conferring an autoimmune diathesis in general and others determining precisely which autoimmune phenotype may result. On this basis it is reasonable to hypothesise that genes shown to be relevant in one autoimmune disease may be of importance in another and therefore offer themselves as potential candidates.

During the last few years striking progress has been made in unravelling the genetic basis of susceptibility to Crohn’s disease. Significant evidence for linkage in the pericentromeric region of chromosome 16 has been found,3 following on from which two independent groups, one using association mapping4 and the other following a candidate gene approach,5 identified the relevant gene as NOD2. Three variants of this gene (IBD8, IBD12, and IBD13) were shown to influence susceptibility to Crohn’s disease. IBD8 is a missense mutation in exon 3 (2023C>T, R675W); IBD12 is a missense mutation in exon 7 (2641G>C, G1881R); and IBD13 is a frameshift variant in exon 10 (2936insC, 980fs981X). Although precise functions of the NOD2 gene are not fully known it is believed to have important immunological activity, particularly in maintaining symbiosis between the gut lining and its commensal bacteria.

Given the established importance of these variants in determining susceptibility to one autoimmune disease (Crohn’s disease), we examined their role in a second by genotyping all three variants in a large number of patients with multiple sclerosis (n = 631) and a cohort of controls (n = 343).

All individuals taking part in this study gave informed written consent for genetic analysis. Each individual gave a venous blood sample from which DNA was extracted using standard methods. Genotyping was undertaken using Applied Biosystems multiplex primer extension assay system (Multiplex SNaPshot). Primers for primary PCR amplification and extension reactions are shown in table 1. Electrophoresis was done on a 3700 DNA analyser with genotyping completed using the GENSCAN/GENOTYPER software systems. Statistical analysis was by χ2 testing.

The observed allele frequencies are shown in table 1. No statistically significant difference in allele frequency was seen for IBD8 (χ2 = 1.57, p = 0.21), IBD12 (χ2 = 0.002, p = 0.96), or IBD13 (χ2 = 2.78, p = 0.10). In each case, the observed allele frequency was commensurate with that previously observed in the Crohn’s disease studies (table 1).

Our results indicate that the NOD2 gene is probably not influencing susceptibility to autoimmune disease in general but is specific for Crohn’s disease.

Table 1

Observed frequency of Crohn’s disease associated alleles in multiple sclerosis


We thank members of the Association of British Neurologists and the Multiple Sclerosis Society of Great Britain and Northern Ireland for notifying patients participating in this genetic analysis of multiple sclerosis. The work was supported by the Wellcome Trust (grant 057097).


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  • Competing intersts: none declared

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