30 July 2007
A new paper in the New England Journal of Medicine (NEJM) reports the results of a genome wide association study (GWA) conducted by members of the International Multiple Sclerosis Genetics Consortium. These results, the latest in a series of highly-powered, large-scale genetic association studies for common, complex diseases, were based on combined data from genetic analysis of more than 12,000 subjects [NEJM July 29 2007, doi: 10.1056/NEJMoa073493 (abstract)]. The initial study looked at the association between more than 300,000 single nucleotide polymorphism (SNP) markers across the genome in over 900 family trios (an individual affected by multiple sclerosis and their parents). This was followed by genotypic analysis of over 600 more family trios, over 2300 further affected subjects and almost 800 control subjects. Two additional control datasets were included in the final combined analysis.
All of the SNPs that showed a significant association with multiple sclerosis (MS) fell within the HLA region, a genetic locus previously linked with the disease by multiple studies. The most strongly associated SNPs were identified within the IL2RA (interleukin-2 receptora) gene, the IL7RA (interleukin-7 receptor α gene) and the major histocompatibility complex (MHC) class II region gene within the HLA-DRA locus; neither the IL2RA nor IL7RA genes have previously been linked with MS risk. The IL-2 receptor has been linked to two other forms of autoimmune disease (type 1 diabetes and autoimmune thyroid disease), whilst the IL-7 receptor is thought to be involved in the regulation specific immune response cells. Together, these results support previous findings that suggest that multiple sclerosis is an autoimmune inflammatory disorder, and that certain variants of genes involved in theregulation of immune responses represent risk factors for the pathogenesis of MS.
Additional reports from the same study published in the journal Nature Genetics discuss the link between the IL7RA gene variant and multiple sclerosis [Gregory SG et al. Nature Genetics 29 July 2007, doi:10.1038/ng2103 (abstract); Lundmark F et al. Nature Genetics 29 July 2007, doi:10.1038/ng2106 (abstract)].
Comment: This study differs from some recently reported GWAs, in that it supports the findings of previous genetic association studies, which also pointed to variations within the MHC genes being most strongly associated with disease risk. It also extends knowledge by identifying two new genetic associations. Although the risks conferred by the two common polymorphisms in the IL2RA and IL7RA genes are very small, and researchers anticipate that many more risk-associated genetic variants will be identified in future studies, this link has provided valuable information about possible pathogenic mechanisms involved in MS, and further underlined the value of large scale genome-wide association studies. With increasing capacity to identify genetic polymorphisms that individually confer minimal disease risk, the future challenge is likely to be making sense of these data by relating it to possible disease pathways and therapeutic interventions.