@article{c554c6a0586a4106b5fd64c6294105a0,
title = "HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry",
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.",
author = "Pravitt Gourh and Safran, {Sarah A.} and Theresa Alexander and Boyden, {Steven E.} and Morgan, {Nadia D.} and Shah, {Ami A.} and Mayes, {Maureen D.} and Ayo Doumatey and Bentley, {Amy R.} and Daniel Shriner and Domsic, {Robyn T.} and Medsger, {Thomas A.} and Ramos, {Paula S.} and Silver, {Richard M.} and Steen, {Virginia D.} and John Varga and Vivien Hsu and Saketkoo, {Lesley Ann} and Elena Schiopu and Dinesh Khanna and Gordon, {Jessica K.} and Brynn Kron and Criswell, {Lindsey A.} and Heather Gladue and Derk, {Chris T.} and Bernstein, {Elana J.} and Bridges, {S. Louis} and Shanmugam, {Victoria K.} and Kolstad, {Kathleen D.} and Lorinda Chung and Suzanne Kafaja and Reem Jan and Marcin Trojanowski and Avram Goldberg and Korman, {Benjamin D.} and Steinbach, {Peter J.} and Chandrasekharappa, {Settara C.} and Mullikin, {James C.} and Adebowale Adeyemo and Charles Rotimi and Wigley, {Fredrick M.} and Kastner, {Daniel L.} and Francesco Boin and Remmers, {Elaine F.}",
note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jan,
day = "7",
doi = "10.1073/pnas.1906593116",
language = "English (US)",
volume = "117",
pages = "552--562",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "1",
}