Preface and overview: genetics of SLE; a sine qua non for identification

Clinical manifestations of systemic lupus erythematosus (SLE) are extremely diverse and variable, mainly because SLE is a multi-factorial disease. Variable combinations of contributing genes at multiple loci in individual patients probably result in diverse disease phenotypes. Genes that predispose to SLE are undoubtedly related to key events in pathogenesis, and may involve a variety of genes in immune system. These genes are currently unidentified, mostly because of the complexity of multi-factorial inheritance. Recently, the application of the polymerase chain reaction and the availability of maps of microsatellites have facilitated a genome-wide scan to define the number and locations of genes for complex traits. However, extensive genetic heterogeneities and polymorphisms and complex modes of inheritance of disease phenotypes have delayed completion of a genome-wide analysis of susceptibility loci for human SLE. Since many SLE-susceptibility genes show low penetrance, several hundred affected sibpairs are assumed to be necessary to show linkages for many of the contributing loci. In this respect, studies of polymorphisms and functions of candidate genes suggested based on studies on murine models may contribute to studies on SLE patients and their relatives. Major genetic loci have been mostly identified in SLE-prone mouse strains. Nevertheless, identity of natures, functions and roles in the pathogenesis of SLE remains undetermined. Considering the possibility of clustering of susceptibility loci in a particular chromosomal interval, the final goal for identification of susceptibility genes will largely depend on the generation of mutant SLE-prone mice with homologous recombination of the potential target gene. Extensive reviews collected here are expected to form the basis for identification of target genes and for clarification of the genetic mechanisms underlying SLE.