HLA motifs associated with autoantibody production and cross-racial similarities in systemic sclerosis using the SFVT approach (93.37)

Abstract

Abstract Significant associations have been found between specific HLA alleles and a variety of autoimmune diseases. Current studies treat each HLA allele as a single complete unit, which does not distinguish the parts of the molecule associated with disease or the production of particular autoantibodies. This approach also cannot uncover similarities in different predisposing alleles across races. We previously developed a novel approach for genetic association analysis in which HLA proteins are broken down into smaller sequence features (SF) with polymorphisms in these features categorized as variant types (VT). Using the SFVT approach, we analyzed DRB1, DQA1 and DQB1 typing data in a cohort of patients with Systemic Sclerosis (SSc) and demographically matched controls. We found similar predisposing and protective SFVTs in African Americans, Caucasians and Hispanics (e.g. the predisposing 67F_70D_71R peptide binding/TCR recognition motif) despite differences in the frequencies of predisposing and protective alleles that carry these SFVTs in these populations. In addition, we found that SFVTs that differ by only a few amino acids are significantly associated with the presence or absence of different autoantibodies in SSc patients (e.g. the antigen binding motif 9W_57D_60Y_67L was associated with anti-centromere, while 9E_57D_60Y_67F was associated with anti-topoisomerase). These results highlight the ability of the SFVT approach to shed light on the role of HLA in autoimmune disease.