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Abstract  Multiple sclerosis (MS) is an autoimmune disease with central nervous system pathology. An underlying genetic contribution to MS pathogenesis is suggested by familial clustering of cases and the frequent occurrence of MS in specific groups with a common ancestral history (particularly those of northern European origin) compared with others. Recurrence risk estimates in multi-case families, combined with observations of twin concordance and empirical data predict that the MS-prone genotype results primarily from multiple independent or interacting polymorphic genes, each exerting a small or moderate effect. Equally significant, it is also likely that genetic heterogeneity exists, meaning that specific genes influence susceptibility and pathogenesis in some affected but not in others. Genes encoding antigen-presenting molecules within the HLA region in chromosome 6p21, account for the largest part of the genetic risk for MS and until recently, the rest of MS genetics constituted an impenetrable black box. The past few years have seen real progress in the development of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and, as a result, multiple non-HLA allelic variants affecting MS susceptibility were identified and convincingly replicated. Their incomplete penetrance and moderate individual effect probably reflects interactions with other genes, post-transcriptional regulatory mechanisms, and significant environmental influences.

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