Mapping of Susceptibility Genes for Systemic Lupus Erythematosus (sle)

Systemic lupus erythematosus (SLE) is an autoimmune disease with variable and diverse clinical manifestations. Its etiology is unclear, but based on epidemiological and animal studies both genetic and environmental factors are involved. Several candidate susceptibility loci have been identified in case-control association studies and in linkage studies (Kelly et al. 2002). Recent genome wide scans in different ethnic groups have suggested a number of susceptibility loci for SLE, but no gene has been identified as yet (Moser et al. 1998; Gaffney et al. 1998 and 2000; Shai et al.1999; Gray-McGuire et al. 2000; Lindqvist et al. 2000). These studies clearly indicate that multiple genes are involved in conferring susceptibility to SLE. In this nationwide study, we first ascertained a large group of patients and their relatives for a genetic study, characterized their phenotypes, conducted a genome-wide scan for SLE susceptibility loci with Finnish multiplex families, and followed the linkage study with a genetic association study in the selected region. The clinical characteristics were evaluated for all identified families, 53 of which were multiply affected by SLE. There were no differences in clinical and laboratory findings between sporadic and familial cases, suggesting that familial and sporadic SLE are the same entity. As an attempt to stratify the families according to a restricted subphenotype, we investigated the presence of antiphospholipid antibodies (aPLs). However, this subphenotype did not cluster in any families, thus providing no tools to subdivide the pedigrees into more homogeneous subsets. The genome-wide scan was performed on 35 multiplex families. We detected suggestive linkage in regions of chromosomes 6q and 14q, as well as to the HLA region on chromosome 6p. The 14q locus and a partially overlapping region on chromosome 6q have been implicated previously. To obtain additional evidence for susceptibility loci on 6q and 14q, and in order to refine their positions, we added 31 more families from a sub-isolate in central eastern Finland (Savo region), in which founder effects have been noted previously (Nyström-Lahti et al. 1994; Höglund et al. 1995). We performed fine-mapping, at 1 cM density, across the suggestive regions for linkage, and found evidence of excess sharing of a haplotype on chromosome 14q and excess transmission of a haplotype on chromosome 6q. These results confirmed the evidence for SLE susceptibility loci on chromosome 14q and 6q. Moreover, our results are compatible with the concept of a founder effect for susceptibility genes in SLE in central eastern Finland, and suggest a path to the identification of the putative susceptibility genes.