The genetics of systemic lupus erythematosus : Mapping of susceptibility loci for human SLE

Sammanfattning: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting organs such as skin, jointsand kidneys. Characteristic for the disease is increased production of autoantibodies, in particular against dsDNA. Previous studies of SLE in mouse models and in humans indicate polygenic inheritance and genetic heterogeneity.For the purpose of genome scanning, we designed a set of chromosome specific panels of microsatellite markers for efficient genotyping. The 391 microsatellite markers, available from the Weber set 6.0 (CHLC), were organized according to chromosome and size of amplification products and were assigned fluorescent color for detection by ABI automated sequencers. The efficiency of the markers was evaluated regarding amplification of genomic DNA extracted from peripheral blood, formalin-fixed biopsy and pieces of hair. We conducted a genome wide search for SLE susceptibility loci in multi-case families from Iceland and Sweden using two-point linkage analysis. Prior to the analysis, the family material was stratified based on the presence of the deficiency of complement component C4A, a potential risk factor for susceptibility to SLE. Eighteen chromosomal regions with LOD scores > 1.0 were identified, some of which were shared between the two population groups. The most pronounced linkage was found on chromosome 2q37, with a LOD score of 4.24 in the combined family material. The locus was denoted hSLE1.To further evaluate the 2q37 region we analyzed additional microsatellite markers in families from Iceland; Sweden and Norway. The highest two-point lod score was obtained for the marker D2S125 and the multipoint analysis indicated the position of the locus between D2S125 and D2S2986 with a peak lod score of 5.29 at D2S125. No evidence of linkage was found in a set of families from Mexico. We also investigated the gene encoding interleukin 10 (IL-10) on chromosome 1, previously suggested to be a candidate gene for susceptibility to SLE. A microsatellite marker in the IL-10 promotor region was studied in 330 Mexican SLE patients and 368 ethnically matched controls for association to the disease. In addition, linkage to the same marker was evaluated in multi-case families from Iceland, Sweden and Mexico. No association or linkage was found.