Old Suspects Found Guilty — The First Genome Profile of Multiple Sclerosis

Leena Peltonen, M.D., Ph.D.
High-resolution genomewide association studies using panels of 300,000 to 1 million single-nucleotide polymorphisms (SNPs) aim to define genetic risk profiles of common diseases. These studies herald a fundamentally new opportunity to explore human biology and medicine, since they are unbiased by previous hypotheses or assumptions about the nature of genes that influence complex diseases. Underscoring the importance of this approach is the fact that many genetic variants identified as risk factors in type 2 diabetes and Crohn's disease by such studies have been localized to previously unsuspected pathways, to genes without a known function, or to noncoding regions of genes.(...)

In this issue of the Journal, Hafler et al.⁵* describe the outcome of the first effort of the International Multiple Sclerosis Genetics Consortium to define the genetic profile underlying a predisposition to multiple sclerosis. This large-scale association study, a joint analysis of an impressive data set of more than 12,000 subjects, supports the prediction of multiple risk alleles.

The data strongly support the dominance of the HLA locus in the genetic background of patients with multiple sclerosis but also indicate the involvement of two interesting genes: IL2RA, which encodes the alpha subunit of the interleukin-2 receptor (also known as CD25) on chromosome 10p15, and IL7RA, which encodes the alpha chain of the interleukin-7 receptor on chromosome 5p13. Both of the genes scored as next-best signals in the final data analysis.

We should remember that, by definition, genomewide association studies that rely on common SNPs monitor only common alleles, but there is so much more in the genetic risk profiles behind common diseases such as multiple sclerosis. We need to define the full allelic diversity of the "suspicious genes" that are initially identified by genomewide studies. By sequencing the potential risk alleles in large study samples, we will probably encounter rare, high-impact alleles with critical importance for disease risk in some families or patients. The lessons learned from studies of genetic risk variants like BRCA1 and BRCA2, which are rare alleles with a high impact but which explain only a small fraction of breast cancers, will be instructive for our thinking about other complex diseases. The somewhat disappointing outcome with respect to the attributable risk conferred by the SNPs sampled in IL2RA and IL7RA indicates that other types of genome variants should be sought. Without a doubt, the multiple sclerosis community will soon be informed about the systematic scans for copy-number variations or other more complex changes in the genomic architecture of risk alleles for multiple sclerosis.

*Aqueles que quiserem o artigo da NEJM em formato pdf, escrevam para psrcoelho@gmail.com