The genetics of complex autoimmune diseases: non-MHC susceptibility genes

Susceptibility to complex autoimmune diseases (AIDs) is a multigenic phenotype affected by a variety of genetic and environmental or stochastic factors. After over a decade of linkage analyses, the identification of non-major histocompatibility complex (non-MHC) susceptibility alleles has proved to be difficult, predominantly because of extensive genetic heterogeneity and possible epistatic interactions among the multiple genes required for disease development. Despite these difficulties, progress has been made in elucidating the genetic mechanisms that influence the inheritance of susceptibility, and the pace of gene discovery is accelerating. An intriguing new finding has been the colocalization of several AID susceptibility genes in both rodent models and human linkage studies. This may indicate that several susceptibility alleles affect multiple AIDs, or alternatively that genomic organization has resulted in the clustering of many immune system genes. The completion of the human genome sequence, coupled with the imminent completion of the mouse genome, should yield key information that will dramatically enhance the rate of gene discovery in complex conditions such as AID susceptibility.