Update on the genetics of the idiopathic inflammatory myopathies

A number of lines of investigation suggest that, as is likely the case for other autoimmune diseases, the idiopathic inflammatory myopathies (IIM) dev elop as a result of specific environmental exposures in genetically suscept ible individuals. Current data imply that multiple genes are involved in th e etiology of these complex disorders. Targeted gene studies and whole geno me approaches have begun to identify several genetic risk factors for autoi mmune diseases, but the rarity and heterogeneity of the IIM have limited ou r knowledge of their associated genes. Current findings suggest that human leukocyte antigen (HLA) genes on chromosome 6, particularly HLA DRB1*0301 a nd the linked allele DQA1*0501, have the strongest associations with all cl inical forms of IIM in white patients. Different HLA alleles, however, may confer risk or protection for myositis in distinct ethnic, serologic, and e nvironmental exposure groups. Non-HLA genetic risk factors, which have been documented for other autoimmune diseases, are now being identified for the IIM. These include polymorphic genes encoding immunoglobulin heavy chains (defined by serologic markers known as Gm allotypes), cytokines and their r eceptors, and certain proteins that accumulate in the myocyte vacuoles of i nclusion body myositis patients. Selected allelic polymorphisms of interleu kin-1 receptor antagonist variable number tandem repeats and genes for tumo r necrosis factor alpha and interleukin-l alpha also have recently been ass ociated with IIM. The pathogenic bases for the differences among the many c linically, pathologically and immunologically defined syndromes known as th e IIM will be elucidated through a better understanding of the multiple gen es that define risks for their development, as well as through investigatio ns of gene-gene and gene-environment interactions. (C) 2000 Lippincott Will iams & Wilkins. Inc.