Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes
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 ri...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.913196/full |
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| author | Aimee L. Hanson Aimee L. Hanson Joanne Sahhar Gene-Siew Ngian Janet Roddy Jennifer Walker Wendy Stevens Wendy Stevens Mandana Nikpour Mandana Nikpour Shervin Assassi Susanna Proudman Susanna Proudman Maureen D. Mayes Tony J. Kenna Matthew A. Brown Matthew A. Brown |
| author_facet | Aimee L. Hanson Aimee L. Hanson Joanne Sahhar Gene-Siew Ngian Janet Roddy Jennifer Walker Wendy Stevens Wendy Stevens Mandana Nikpour Mandana Nikpour Shervin Assassi Susanna Proudman Susanna Proudman Maureen D. Mayes Tony J. Kenna Matthew A. Brown Matthew A. Brown |
| author_sort | Aimee L. Hanson |
| collection | DOAJ |
| description | 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 HLA 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 KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA 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 HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, 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’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc. |
| first_indexed | 2024-04-13T21:32:22Z |
| format | Article |
| id | doaj.art-67d79eafa0f8430bac0e6f529a57a82d |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-13T21:32:22Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-67d79eafa0f8430bac0e6f529a57a82d2022-12-22T02:29:06ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-06-011310.3389/fgene.2022.913196913196Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease SubtypesAimee L. Hanson0Aimee L. Hanson1Joanne Sahhar2Gene-Siew Ngian3Janet Roddy4Jennifer Walker5Wendy Stevens6Wendy Stevens7Mandana Nikpour8Mandana Nikpour9Shervin Assassi10Susanna Proudman11Susanna Proudman12Maureen D. Mayes13Tony J. Kenna14Matthew A. Brown15Matthew A. Brown16Department of Medicine, University of Queensland, Brisbane, QLD, AustraliaDepartment of Medicine, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, Clayton and Monash Health, Monash University, Melbourne, VIC, AustraliaDepartment of Medicine, Clayton and Monash Health, Monash University, Melbourne, VIC, AustraliaDepartment of Rheumatology, Royal Perth Hospital, Perth, WA, AustraliaRheumatology Unit, Flinders Medical Centre, Adelaide, SA, AustraliaDepartment of Medicine, University of Melbourne, St Vincent’s Hospital, Melbourne, VIC, AustraliaDepartment of Rheumatology, St Vincent’s Hospital, Melbourne, VIC, AustraliaDepartment of Medicine, University of Melbourne, St Vincent’s Hospital, Melbourne, VIC, AustraliaDepartment of Rheumatology, St Vincent’s Hospital, Melbourne, VIC, AustraliaDivision of Rheumatology, University of Texas, Houston, TX, United StatesRheumtology Unit, Royal Adelaide Hospital, Adelaide, SA, Australia0Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaDivision of Rheumatology, University of Texas, Houston, TX, United States1Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia2Genomics England, Charterhouse Square, London, United Kingdom3Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King’s College London, London, United KingdomSystemic 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 HLA 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 KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA 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 HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, 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’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.https://www.frontiersin.org/articles/10.3389/fgene.2022.913196/fullsystemic sclerosis (scleroderma)HLA association and diseasehuman disease geneticskiller immunoglobulin like receptor (KIR)immunogenetics |
| spellingShingle | Aimee L. Hanson Aimee L. Hanson Joanne Sahhar Gene-Siew Ngian Janet Roddy Jennifer Walker Wendy Stevens Wendy Stevens Mandana Nikpour Mandana Nikpour Shervin Assassi Susanna Proudman Susanna Proudman Maureen D. Mayes Tony J. Kenna Matthew A. Brown Matthew A. Brown Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes Frontiers in Genetics systemic sclerosis (scleroderma) HLA association and disease human disease genetics killer immunoglobulin like receptor (KIR) immunogenetics |
| title | Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes |
| title_full | Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes |
| title_fullStr | Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes |
| title_full_unstemmed | Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes |
| title_short | Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes |
| title_sort | contribution of hla and kir alleles to systemic sclerosis susceptibility and immunological and clinical disease subtypes |
| topic | systemic sclerosis (scleroderma) HLA association and disease human disease genetics killer immunoglobulin like receptor (KIR) immunogenetics |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.913196/full |
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