{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:31:27Z","timestamp":1787859087585,"version":"build-2784847793"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of\n                    <jats:italic>HLA<\/jats:italic>\n                    inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the\n                    <jats:italic>KIR<\/jats:italic>\n                    locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of\n                    <jats:italic>KIR-HLA<\/jats:italic>\n                    epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype\n                    <jats:italic>HLA-B*44:03-HLA-C*16:01<\/jats:italic>\n                    \u00a0at genome-wide significance (GWS). We further report statistically significant\n                    <jats:italic>HLA<\/jats:italic>\n                    associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of\n                    <jats:italic>HLA-DRB1*15:01<\/jats:italic>\n                    , previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual\u2019s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2022.913196","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T04:27:21Z","timestamp":1654662441000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes"],"prefix":"10.3389","volume":"13","author":[{"given":"Aimee L.","family":"Hanson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Sahhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene-Siew","family":"Ngian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Roddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandana","family":"Nikpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shervin","family":"Assassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Proudman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen D.","family":"Mayes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony J.","family":"Kenna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1136\/annrheumdis-2021-219884","article-title":"Comprehensive Analysis of the Major Histocompatibility Complex in Systemic Sclerosis Identifies Differential HLA Associations by Clinical and Serological Subtypes","volume":"80","author":"Acosta-Herrera","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1136\/ard.2009.111906","article-title":"Major Histocompatibility Complex (MHC) Class II Alleles, Haplotypes and Epitopes Which Confer Susceptibility or Protection in Systemic Sclerosis: Analyses in 1300 Caucasian, African-American and Hispanic Cases and 1000 Controls","volume":"69","author":"Arnett","year":"2010","journal-title":"Ann. Rheumatic Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"R166","DOI":"10.1186\/ar3125","article-title":"Predictors of Interstitial Lung Disease in Early Systemic Sclerosis: a Prospective Longitudinal Study of the GENISOS Cohort","volume":"12","author":"Assassi","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1002\/1529-0131(199906)42:6<1168::aid-anr13>3.0.co;2-l","article-title":"Production of Type 2 Cytokines by CD8+ Lung Cells Is Associated with Greater Decline in Pulmonary Function in Patients with Systemic Sclerosis","volume":"42","author":"Atamas","year":"1999","journal-title":"Arthritis & Rheumatism"},{"key":"B6","doi-asserted-by":"publisher","first-page":"854","DOI":"10.4049\/jimmunol.179.2.854","article-title":"KIR2DS1-Positive NK Cells Mediate Alloresponse Against the C2 HLA-KIR Ligand Group In Vitro","volume":"179","author":"Chewning","year":"2007","journal-title":"J. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/ar3204","article-title":"Promise and Pitfalls of the Immunochip","volume":"13","author":"Cortes","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/ng.2667","article-title":"Identification of Multiple Risk Variants for Ankylosing Spondylitis through High-Density Genotyping of Immune-Related Loci","volume":"45","author":"Cortes","year":"2013","journal-title":"Nat. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1155\/2013\/301415","article-title":"HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients","volume":"35","author":"Del Rio","year":"2013","journal-title":"Dis. Markers"},{"key":"B10","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1093\/rheumatology\/37.2.201","article-title":"HLA Associations in Three Mutually Exclusive Autoantibody Subgroups in UK Systemic Sclerosis Patients","volume":"37","author":"Fanning","year":"1998","journal-title":"Rheumatology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.jneuroim.2010.08.004","article-title":"KIRs and Their HLA Ligands in Remitting-Relapsing Multiple Sclerosis","volume":"229","author":"Fusco","year":"2010","journal-title":"J. Neuroimmunol."},{"key":"B12","first-page":"1481","article-title":"HLA Markers for Susceptibility and Expression in Scleroderma","volume":"32","author":"Gladman","year":"2005","journal-title":"J. Rheumatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"D783","DOI":"10.1093\/nar\/gkz1029","article-title":"Allele Frequency Net Database (AFND) 2020 Update: Gold-Standard Data Classification, Open Access Genotype Data and New Query Tools","volume":"48","author":"Gonzalez-Galarza","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1073\/pnas.1906593116","article-title":"HLA and Autoantibodies Define Scleroderma Subtypes and Risk in African and European Americans and Suggest a Role for Molecular Mimicry","volume":"117","author":"Gourh","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1084\/jem.183.4.1817","article-title":"Heterogeneous Phenotypes of Expression of the NKB1 Natural Killer Cell Class I Receptor Among Individuals of Different Human Histocompatibility Leukocyte Antigens Types Appear Genetically Regulated, but Not Linked to Major Histocompatibililty Complex Haplotype","volume":"183","author":"Gumperz","year":"1996","journal-title":"J. Exp. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1008906","DOI":"10.1371\/journal.pgen.1008906","article-title":"Epistatic Interactions Between Killer Immunoglobulin-Like Receptors and Human Leukocyte Antigen Ligands Are Associated with Ankylosing Spondylitis","volume":"16","author":"Hanson","year":"2020","journal-title":"PLoS Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/ar628","article-title":"The Clinical Relevance of Autoantibodies in Scleroderma","volume":"5","author":"Ho","year":"2003","journal-title":"Arthritis Res. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/gene.2016.5","article-title":"The Killer Immunoglobulin-Like Receptor KIR3DL1 in Combination with HLA-Bw4 Is Protective Against Multiple Sclerosis in African Americans","volume":"17","author":"Hollenbach","year":"2016","journal-title":"Genes Immun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1111\/j.0022-202x.2005.23767.x","article-title":"Abnormal Natural Killer Cell Function in Systemic Sclerosis: Altered Cytokine Production and Defective Killing Activity","volume":"125","author":"Horikawa","year":"2005","journal-title":"J. Investigative Dermatology"},{"key":"B20","first-page":"2454","article-title":"Influence of Clinical Features, Serum Antinuclear Antibodies, and Lung Function on Survival of Patients with Systemic Sclerosis","volume":"28","author":"Jacobsen","year":"2001","journal-title":"J. Rheumatol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/acr2.11398","article-title":"The Effect of Anti-Scl-70 Antibody Determination Method on its Predictive Significance for Interstitial Lung Disease Progression in Systemic Sclerosis","volume":"4","author":"Jandali","year":"2022","journal-title":"ACR Open Rheumatol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1101\/gr.137976.112","article-title":"Copy Number Variation Leads to Considerable Diversity for B but Not A Haplotypes of the Human KIR Genes Encoding NK Cell Receptors","volume":"22","author":"Jiang","year":"2012","journal-title":"Genome Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1136\/annrheumdis-2020-218881","article-title":"Anti-Centromere Antibodies Target Centromere-Kinetochore Macrocomplex: A Comprehensive Autoantigen Profiling","volume":"80","author":"Kajio","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"B24","first-page":"97","article-title":"Occupational Exposure to Solvents and Gender-Related Risk of Systemic Sclerosis: A Metaanalysis of Case-Control Studies","volume":"34","author":"Kettaneh","year":"2007","journal-title":"J. Rheumatol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1126\/science.1097670","article-title":"HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection","volume":"305","author":"Khakoo","year":"2004","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1136\/ard.54.12.983","article-title":"HLA Class II Genes Associated with Anticentromere Antibody in Japanese Patients with Systemic Sclerosis (Scleroderma)","volume":"54","author":"Kuwana","year":"1995","journal-title":"Ann. Rheumatic Dis."},{"key":"B27","first-page":"1573","article-title":"Criteria for the Classification of Early Systemic Sclerosis","volume":"28","author":"Leroy","year":"2001","journal-title":"J. Rheumatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1172\/jci107827","article-title":"Increased Collagen Synthesis by Scleroderma Skin Fibroblasts In Vitro A Possible Defect in the Regulation or Activation of the Scleroderma Fibroblast","volume":"54","author":"Leroy","year":"1974","journal-title":"J. Clin. Invest."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.jid.2016.11.037","article-title":"Skin-Resident Effector Memory CD8+CD28- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis","volume":"137","author":"Li","year":"2017","journal-title":"J. Investigative Dermatology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0146086","DOI":"10.1371\/journal.pone.0146086","article-title":"Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis","volume":"11","author":"Littera","year":"2016","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e2","DOI":"10.1371\/journal.pmed.0030002","article-title":"Antibodies Against Human Cytomegalovirus in the Pathogenesis of Systemic Sclerosis: A Gene Array Approach","volume":"3","author":"Lunardi","year":"2006","journal-title":"PLoS Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1007\/s10067-016-3526-0","article-title":"Analysis of Killer Cell Immunoglobulin-Like Receptors (KIRs) and Their HLA Ligand Genes Polymorphisms in Iranian Patients with Systemic Sclerosis","volume":"36","author":"Mahmoudi","year":"2017","journal-title":"Clin. Rheumatol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"8492","DOI":"10.1073\/pnas.86.21.8492","article-title":"Determination of an Epitope of the Diffuse Systemic Sclerosis Marker Antigen DNA Topoisomerase I: Sequence Similarity with Retroviral P30gag Protein Suggests a Possible Cause for Autoimmunity in Systemic Sclerosis","volume":"86","author":"Maul","year":"1989","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.ajhg.2013.12.002","article-title":"Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis","volume":"94","author":"Mayes","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"R172","DOI":"10.1186\/ar3495","article-title":"Frequency of Disease-Associated and Other Nuclear Autoantibodies in Patients of the German Network for Systemic Scleroderma: Correlation with Characteristic Clinical Features","volume":"13","author":"Mierau","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1038\/s41467-021-22359-x","article-title":"Structural Plasticity of KIR2DL2 and KIR2DL3 Enables Altered Docking Geometries Atop HLA-C","volume":"12","author":"Moradi","year":"2021","journal-title":"Nat. Commun."},{"key":"B37","doi-asserted-by":"crossref","DOI":"10.1101\/091009","volume-title":"Practical Use of Methods for Imputation of HLA Alleles from SNP Genotype Data","author":"Motyer","year":"2016"},{"key":"B38","doi-asserted-by":"publisher","first-page":"5213","DOI":"10.1128\/jvi.03586-14","article-title":"Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1","volume":"89","author":"O'connor","year":"2015","journal-title":"J. Virol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1111\/j.1399-0039.2006.762_6.x","article-title":"KIRs and Autoimmune Disease: Studies in Systemic Lupus Erythematosus and Scleroderma","volume":"69","author":"Pellett","year":"2007","journal-title":"Tissue antigens"},{"key":"B40","volume-title":"R: A Language and Environment for Statistical Computing","year":"2021"},{"key":"B41","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1002\/art.11113","article-title":"Evidence-based Guidelines for the Use of Immunologic Tests: Anticentromere, Scl-70, and Nucleolar Antibodies","volume":"49","author":"Reveille","year":"2003","journal-title":"Arthritis & Rheumatism"},{"key":"B42","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1053\/sarh.2001.20268","article-title":"Systemic Sclerosis in 3 US Ethnic Groups: A Comparison of Clinical, Sociodemographic, Serologic, and Immunogenetic Determinants","volume":"30","author":"Reveille","year":"2001","journal-title":"Seminars Arthritis Rheumatism"},{"key":"B43","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1111\/j.1365-2249.2010.04095.x","article-title":"Killer Cell Immunoglobulin-Like Receptor (KIR) Genes in Systemic Sclerosis","volume":"160","author":"Salim","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"102574","DOI":"10.1016\/j.jaut.2020.102574","article-title":"Longitudinal Analysis of T-Cell Receptor Repertoires Reveals Persistence of Antigen-Driven CD4+ and CD8+ T-Cell Clusters in Systemic Sclerosis","volume":"117","author":"Servaas","year":"2021","journal-title":"J. Autoimmun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.3899\/jrheum.090377","article-title":"Association of HLA Class II Genes with Systemic Sclerosis in Spanish Patients","volume":"36","author":"Sime\u00f3n","year":"2009","journal-title":"J. Rheumatol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1136\/oem.42.12.838","article-title":"Silica, Silicosis, and Progressive Systemic Sclerosis","volume":"42","author":"Sluis-Cremer","year":"1985","journal-title":"Occup. Environ. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1002\/art.1780310207","article-title":"Clinical Correlations and Prognosis Based on Serum Autoantibodies in Patients with Systemic Sclerosis","volume":"31","author":"Steen","year":"1988","journal-title":"Arthritis & Rheumatism"},{"key":"B48","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1002\/art.1780230510","article-title":"Preliminary Criteria for the Classification of Systemic Sclerosis (Scleroderma). Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee","volume":"23","year":"1980","journal-title":"Arthritis Rheum."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1016\/s0140-6736(63)92920-9","article-title":"Antinuclear and Precipitating Autoantibodies in Progressive Systemic Sclerosis","volume":"282","author":"Swanson Beck","year":"1963","journal-title":"Lancet"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1002\/art.41248","article-title":"Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma","volume":"72","author":"Tiniakou","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.ajhg.2015.09.005","article-title":"Imputation of KIR Types from SNP Variation Data","volume":"97","author":"Vukcevic","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"B51","doi-asserted-by":"crossref","first-page":"571","DOI":"10.4049\/jimmunol.161.2.571","article-title":"Direct Binding and Functional Transfer of NK Cell Inhibitory Receptors Reveal Novel Patterns of HLA-C Allotype Recognition","volume":"161","author":"Winter","year":"1998","journal-title":"J. Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/0198-8859(96)00091-2","article-title":"Skewing of the CDS + T-Cell Repertoire in the Lungs of Patients with Systemic Sclerosis","volume":"48","author":"Yurovsky","year":"1996","journal-title":"Hum. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1186\/s13075-014-0438-8","article-title":"An Immunochip-Based Interrogation of Scleroderma Susceptibility Variants Identifies a Novel Association at DNASE1L3","volume":"16","author":"Zochling","year":"2014","journal-title":"Arthritis Res. Ther."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.913196\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T12:54:03Z","timestamp":1675774443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.913196\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,8]]},"references-count":53,"alternative-id":["10.3389\/fgene.2022.913196"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.913196","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,8]]},"article-number":"913196"}}