Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

摘要

多发性硬化是一种中枢神经系统疾病，涉及炎rn症与神经退化之间的相互作用。尽管人们对此rn进行了很多研究，但决定这种疾病易感性的遗rn传架构仍未确定。一项涉及近1万人(全部为欧rn洲裔)的全基因组关联大型国际合作研究项目，rn证实了以前报告过的与多发性硬化相关的DNArn区域，并识别出另外29个新的易感性位点。进rn一步的分析表明，T-helper细胞的分化与这种rn疾病的发病机理尤为相关。%Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neuro-degenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability~1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals~(2,3), and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk~4. Modestly powered genome-wide association studies (GWAS)~(5,10) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility~11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. 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. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.