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We review the current thinking on the genetic aetiology of multiple sclerosis, new aspects of the influence of genes within the human leucocyte antigen (HLA) complex, how discrete non-HLA genes regulating multiple sclerosis start to be unequivocally demonstrated, and how knowledge from the genetics of experimental models of multiple sclerosis can be used.Different alleles of the class II molecules display a hierarchy of risks including protective effects in multiple sclerosis. In addition, HLA class I genes are associated with the disease. Experimental multiple sclerosis models are regulated by many genes with small effects, more than about 100. Studies in humans suggest a similar situation. Indeed, the two genes unequivocally established, IL2RA and IL7RA, display a low odds ratio in the order of 1.3. We envisage that many more genes of this kind may be unravelled in the years to come.There are hierarchies of influences from class II genes. Class I genes regulate disease as well. The unambiguous demonstration of non-HLA genes also suggests that many other genes impacting multiple sclerosis can be deciphered in the years to come. A complete knowledge of the most important of these may pave the way for more selective therapy and gene–environment studies.