Strategies for Identification of Susceptibility Genes in Complex Autoimmune Diseases

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases affecting 0.05-2% of the population worldwide. Genetic studies detected linkage with SLE in the 2q37 region, and intensive family-based and case-control association studies in several populations identified that allele A of the SNP PD-1.3 located in the immunoreceptor PDCD1 (PD-1) gene, increases risk of the disease by 2.6-fold in Caucasians (p<0.00001) and by 3.5-fold in Mexicans (p=0.0009). The same allele was found to be a risk factor for lupus nephritis, a severe clinical manifestation of SLE. In Swedish and European-American females with SLE, patients with the allele A had nephritis 1.8 times (p=0.01) more often than patients with allele G . Moreover, the allele A was also found 1.8 times (p=0.005) more often in RA patients, negative for the known risk-factors, rheumatoid factor and the shared epitope, than in other groups of patients and controls. Functional studies demonstrated that the mechanism behind the SNP PD-1.3 is related to the disruption of the binding site for RUNX transcription factors in the regulatory region. Expression of the PD-1 and RUNX genes was altered in the activated T cells of SLE patients compared to controls. The Tumor Necrosis Factor Receptor 2 (TNFR 2) gene was studied as a second candidate gene for both SLE and RA. The results of our studies in SLE and RA patients and controls from Sweden and Mexico do not support the association of the polymorphism TNFR 2 M196R with these diseases. Other polymorphisms in this gene and other genes in this region should therefore be studied