Genetic studies on Systemic Lupus Erythematosus A fine mapping and candidate gene approach

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Linkage in the 2q37 region was evaluated using microsatellite markers in multi-case families from Sweden, Iceland and Norway. Both the two-point and the multipoint linkage analysis show highly significant LOD scores (Z=4.51 and 6.03, respectively). Linkage disequilibrium mapping indicates that some association exists in this region. The PDCD1 gene was suggested as a candidate gene within the 2q37 locus due to its importance in immune regulation. Indeed, one haplotype, described by the presence of allele A of the PD1.3 SNP located within intron 4 of this gene, shows linkage to SLE in the Nordic families. The PD1.3A allele is also found to be strongly associated in familiar and sporadic cases of SLE in Europeans and Mexicans. Functional studies further support PD1.3A to be a susceptibility allele for SLE.The 1q23 region, containing the genes for the low affinity Fc? receptors, was fine mapped using single- and multi- case families of various origins. Genetic variants of those genes were analysed and association is found to both the risk alleles of Fc?RIIA and Fc?RIIIA in all families. In these families, a single haplotype carrying both risk alleles is predominantly transmitted to patients with SLE, suggesting a presence of linkage disequilibrium between those two genes. Fc?RIIA and Fc?RIIIA are also found to be associated to SLE and lupus nephritis in a case-control cohort from Sweden. In the same cohort, the PD1.3A allele shows strong association to lupus nephritis. We suggest that there may be an additive effect between Fc?RIIA and PDCD1, since having the disease-associated genotypes at both loci gives an increased risk for developing lupus nephritis.Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder with a complex multifactorial aetiology. Genetic studies suggest that several genes are involved in disease pathogenesis and that extended genetic heterogeneity is present.