The genetics of systemic lupus erythematosus: putting the pieces together

With A,, estimates of 10 to 20 and other evidence of familial aggregation, as well as a monozygotic twin concordance rate >20, systemic lupus erythematosus (SLE) would appear to be a very promising phenotype using modem genetic approaches. Indeed, genetic associations are already known at numerous candidate loci including various HLA alleles, complement component genes, Fcgamma receptors, and others, and murine genetic studies of lupus models have provided additional candidate genes and potential syntenic linkages to evaluate in man. The completed genetic linkage studies performed on various collections of pedigrees multiplex for SLE have identified 60 susceptibility loci with varying degrees of evidence for linkage in man. Seven of these meet or exceed the threshold for significant linkage (LOD greater than or equal to 3.3 or P less than or equal to 0.00005) at 1q22-23, 1q41, 2q37, 4p16, 6p21-11, 16q13 and 17p13. In addition, these linkages usually dominate in one ethnicity or another, suggesting that the responsible polymorphisms, once identified, will also vary by ethnicity. Evidence that these linkages can be reproduced range from outright independent confirmation (1q41, 4p16 and 6p21) to additional suggestive evidence in the genomic region of the purported linkage (1q22-23 and 2q37). The results now available suggest that human lupus genetics are robust and that gene identification should be possible using existing genetic approaches and technologies.