Abstract
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens.We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestrypredominant HLA-DRB1∗08:04 and HLA-DRB1∗11:02 alleles were associated with overall SSc risk, and the HLA-DRB1∗08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestrypredominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1∗13:01 and HLA-DRB1∗07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1∗13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1∗13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
Original language | English (US) |
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Pages (from-to) | 552-562 |
Number of pages | 11 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 117 |
Issue number | 1 |
DOIs | |
State | Published - Jan 7 2020 |
Funding
ACKNOWLEDGMENTS. This study was supported by research funding from the Scleroderma Research Foundation and the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Center for Information Technology of NIH. Data were analyzed using the computational resources of the NIH high-performance computing Biowulf cluster (http://hpc.nih.gov). This work was supported, in part, by a Rheumatology Research Foundation Scientist Development award (P.G. and N.D.M.); NIH Grant T32-AR-048522 (N.D.M.); Chresanthe Staurulakis Memorial Discovery Fund and NIH Grant P30-AR-070254 (N.D.M., A.A.S., and F.M.W.); NIH Grant K01-AR-067280 (P.S.R.); NIH Grant P60-AR-062755 (P.S.R. and R.M.S.); and Nina Ireland Program for Lung Health (F.B.). We thank Dr. Daniella Schwartz for critical reading of the manuscript.
ASJC Scopus subject areas
- General