Exploring the Genetics of SLE with Linkage and Association Analysis

Abstract: The aim with this thesis has been to identify genes involved in the pathogenesis of Systemic Lupus Erythematosus (SLE). SLE is a systemic autoimmune disorder, most likely caused by both several genetic and environmental factors.In order to identify susceptibility loci for the disease we performed linkage analyses on data from 70 families of various ethnic origins. Significant linkage was found in two regions. One region (chromosome 17p12-q11) was linked to SLE in a set of Argentine families. Since the same region had been previously identified in several linkage studies on Multiple Sclerosis patients, we propose that this locus may contain a genetic variant that affects not only SLE, but also autoimmunity in general. The second locus is located on chromosome 4p14-13 and has only been identified in a set of Icelandic families. We suggest that this locus contains a mutation that has been enriched in the Icelandic population due to its population history.The BCL2 gene has been suggested as a candidate gene for SLE. Three markers in this gene were investigated for association with the disease in two different populations. However, no association could be found with any of the markers or when these markers were analysed together as a haplotype. We conclude that the BCL2 gene is not associated with SLE in our material. This result contradicts previously published results of an association between BCL2 and SLE.We suggest that the PD-1 pathway (involved in inhibition of T- and B-cell responses) is an important component in SLE pathogenesis. A regulatory variant in the PD-1 gene had previously been associated with SLE and here we show strong association (p<0.0001) to a haplotype containing SNPs in both PD-L1 and PD-L2.Our results indicate that SLE is a disease caused by several genetic variations that differ between families and populations.