Autoimmune rheumatologic diseases
SNP rs9268832 (C>T variation) is located in HLA-DR locus and has been associated with higher risk of SLE and other autoimmune diseases. In this study, the association between the alleles of rs9268832 and the expression of antigen presentation genes as well as the levels of autoantibodies was accessed in a cohort of SLE patients and normal controls (NC). The frequency of T allele is significantly higher in SLE than NC (Odd=1.7, p=0.0003). SLE patients carrying TT allele of rs9268832 exhibited significantly higher DRB1 and DRB5 genes expression compared with CC allele carriers (p < 0.01). The SLE patients carrying TT allele also showed a dramatic hypomethylation on DRB1 and DRB5 genes compare with CC individuals. Autoantibody profiling revealed that the anti-DNA autoantibodies (anti-dsDNA, anti-ssDNA, anti-Chromatin, anti-nucleosome) were significantly higher in TT allele SLE patients compared with CC or CT allele SLEs (p < 0.05). The DNA fragment containing TT allele from SLE showed more than 2 times higher enhancer activity than the CC allele fragment by a luciferase activation assay. We further confirmed that the TT allele DNA fragment exhibited higher binding activity with transcription factor GABPα by gel electrophoresis mobility shift assay (EMSA). In conclusion, the rs9268832 is a potential functional variant which may enhance the expression of antigen presenting genes HLA-DRB1 and DRB5 by modulating the binding activity with transcription factor GABPα. The hyper expression of the antigen presenting genes could be associated with initial breach in immune tolerance to self-antigens in the risk population.
Center for Immunology, University of Texas Southwestern Medical Center