Researchers Find 29 New Genetic Variants Associated with Multiple Sclerosis
International consortium claims results confirm MS is primarily an immunological disease.!--h2>
Researchers have identified 29 new genetic variants implicated in susceptibility to multiple sclerosis (MS). The International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium carried out what they claim is the largest ever genome-wide association study (GWAS) for MS.
Their results confirmed 23 previously reported genetic associations and suggested that many of the newly identified risk-related genes are immune system-related and in particular implicate T-helper cell differentiation in the pathogenesis of MS.
Lead authors Alastair Compston, M.D., at the U.K.’s University of Cambridge, and Peter Donnelly, M.D., at the University of Oxford Wellcome Trust Centre for Human Genetics, and colleagues, report their findings in Nature in a paper titled “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.”
The GWAS evaluated genetic data from 9,772 cross-population MS patients and 17,376 controls and including 465,434 autosomal SNPs. Of these, 102 were verified using data from previously reported MS GWAS results and the iControl database. For 98 of the 102 SNPs, the same allele was overrepresented in cases compared to controls, including 23 of 26 that have previously been linked with susceptibility to MS.
Another 29 novel associated regions were identified, which implicated numerous genes coding for the cytokine pathway and costimulatory and signal transduction proteins of immunological relevance. The results also highlighted previously reported environmental risk factors such as vitamin D deficiency.
Significantly, for some 30% of the MS-associated regions, the nearest gene to the lead SNP was an immune system gene, and T-helper cell differentiation pathway genes were strongly implicated. DRB1*15:01 had the strongest association with MS among all classical and SNP alleles, with a consistent effect between cohorts.
In fact, five MHC loci (three from class II and a protective class I allele) demonstrated particularly strong evidence of association. “Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region,” the researchers state.
Interestingly, just over one third of the identified loci overlapped with regions that have previously been confirmed as associated with at least one other autoimmune disease, the authors report. “Identifying the basis for genetic susceptibility to any medical condition provides reliable insights into the disease mechanisms,” Dr. Compston comments.
“Our research settles a longstanding debate on what happens first in the complex sequences of events that leads to disability in multiple sclerosis. It is now clear that multiple sclerosis is primarily an immunological disease. This has important implications for future treatment strategies.”