Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels
Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte...
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Elsevier
2025-06-01
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| Series: | Journal of Translational Autoimmunity |
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| author | Yves Renaudineau Amandine Charras Valentina Natoli Nicolas Congy-Jolivet Sam Haldenby Xuan Liu Yongxiang Fang Eve MD. Smith Michael W. Beresford Christian M. Hedrich Carla Roberts Eslam Al-Abadi Kate Armon Kathryn Bailey Coziana Ciurtin Janet Gardner-Medwin Kirsty Haslam Daniel P. Hawley Alice Leahy Valentina Leone Flora McErlane Gita Modgil Clarissa Pilkington Athimalaipet V. Ramanan Satyapal Rangaraj Phil Riley Arani Sridhar |
| author_facet | Yves Renaudineau Amandine Charras Valentina Natoli Nicolas Congy-Jolivet Sam Haldenby Xuan Liu Yongxiang Fang Eve MD. Smith Michael W. Beresford Christian M. Hedrich Carla Roberts Eslam Al-Abadi Kate Armon Kathryn Bailey Coziana Ciurtin Janet Gardner-Medwin Kirsty Haslam Daniel P. Hawley Alice Leahy Valentina Leone Flora McErlane Gita Modgil Clarissa Pilkington Athimalaipet V. Ramanan Satyapal Rangaraj Phil Riley Arani Sridhar |
| author_sort | Yves Renaudineau |
| collection | DOAJ |
| description | Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied. Methods: High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement C2) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh). Results: Although important ancestral recombination was reported for HLA-DR2 and -DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1∗15:01, DQA∗01:02, DQB1∗06:02; DR3h: C∗07:02 [Asian], B∗08:01, C2 rs9332730 [Asian], DRB1∗03:01). HLA-DR7 haplotypes (DRB1∗07:01, OR = 0.44, 95 % CI:0.27–0.72, p = 0.0004; DQA1∗02:01, OR = 0.34, 95 % CI:0.21–0.56, p = 1.8 × 10−6) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C∗07:02 and integration of the C2 rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1∗01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A∗03:01P was observed across ancestries. Conclusion: Genetic variation in the HLA cluster associates with organ domain involvement (hematological) and complement levels in jSLE. Lupus-associated HLA haplotypes vary between ancestral groups, underscoring the importance of multi-ancestral approaches to genetic studies in SLE and other autoimmune/inflammatory diseases. |
| format | Article |
| id | doaj-art-b9dfcc18cf09422ebf28dd2f1ba4a362 |
| institution | OA Journals |
| issn | 2589-9090 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Translational Autoimmunity |
| spelling | doaj-art-b9dfcc18cf09422ebf28dd2f1ba4a3622025-08-20T02:30:55ZengElsevierJournal of Translational Autoimmunity2589-90902025-06-011010026810.1016/j.jtauto.2025.100268Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levelsYves Renaudineau0Amandine Charras1Valentina Natoli2Nicolas Congy-Jolivet3Sam Haldenby4Xuan Liu5Yongxiang Fang6Eve MD. Smith7Michael W. Beresford8Christian M. Hedrich9Carla Roberts10Eslam Al-Abadi11Kate Armon12Kathryn Bailey13Coziana Ciurtin14Janet Gardner-Medwin15Kirsty Haslam16Daniel P. Hawley17Alice Leahy18Valentina Leone19Flora McErlane20Gita Modgil21Clarissa Pilkington22Athimalaipet V. Ramanan23Satyapal Rangaraj24Phil Riley25Arani Sridhar26Immunology Department Laboratory, Referral Medical Biology Laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Centre, France; INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France; Corresponding author. Immunology Department Laboratory, Referral Medical Biology Laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Centre, FranceDepartment of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United KingdomDepartment of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United Kingdom; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli Studi di Genova, Genoa, Italy; UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, Genoa, ItalyImmunology Department Laboratory, Referral Medical Biology Laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Centre, France; CRCT, INSERM, UMR, 1037, University Toulouse III, Toulouse, FranceCentre for Genomic Research, Shared Research Facilities, University of Liverpool, United KingdomCentre for Genomic Research, Shared Research Facilities, University of Liverpool, United KingdomCentre for Genomic Research, Shared Research Facilities, University of Liverpool, United KingdomDepartment of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United Kingdom; Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, United KingdomDepartment of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United Kingdom; Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, United KingdomDepartment of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United Kingdom; Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom; Corresponding author. Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United KingdomDepartment of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, United KingdomDepartment of Rheumatology, Birmingham Children's Hospital, Birmingham, United KingdomDepartment of Paediatric Rheumatology, Cambridge University Hospitals, Cambridge, United KingdomDepartment of Paediatric Rheumatology, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomCentre for Adolescent Rheumatology, University College London, London, United KingdomDepartment of Child Health, University of Glasgow, Glasgow, United KingdomDepartment of Paediatrics, Bradford Royal Infirmary, Bradford, United KingdomDepartment of Paediatric Rheumatology, Sheffield Children's Hospital, Sheffield, United KingdomDepartment of Paediatric Rheumatology, Southampton General Hospital, Southampton, United KingdomDepartment of Paediatric Rheumatology, Leeds Children Hospital, Leeds, United KingdomPaediatric Rheumatology, Great North Children's Hospital, Royal Victoria Infirmary, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United KingdomDepartment of Paediatrics, Musgrove Park Hospital, Taunton, United KingdomDepartment of Paediatric Rheumatology, Great Ormond Street Hospital, London, United KingdomUniversity Hospitals Bristol NHS Foundation Trust & Bristol Medical School, University of Bristol, Bristol, United KingdomDepartment of Paediatric Rheumatology, Nottingham University Hospitals, Nottingham, United KingdomDepartment of Paediatric Rheumatology, Royal Manchester Children's Hospital, Manchester, United KingdomDepartment of Paediatrics, Leicester Royal Infirmary, Leicester, United KingdomObjective: Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied. Methods: High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement C2) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh). Results: Although important ancestral recombination was reported for HLA-DR2 and -DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1∗15:01, DQA∗01:02, DQB1∗06:02; DR3h: C∗07:02 [Asian], B∗08:01, C2 rs9332730 [Asian], DRB1∗03:01). HLA-DR7 haplotypes (DRB1∗07:01, OR = 0.44, 95 % CI:0.27–0.72, p = 0.0004; DQA1∗02:01, OR = 0.34, 95 % CI:0.21–0.56, p = 1.8 × 10−6) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C∗07:02 and integration of the C2 rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1∗01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A∗03:01P was observed across ancestries. Conclusion: Genetic variation in the HLA cluster associates with organ domain involvement (hematological) and complement levels in jSLE. Lupus-associated HLA haplotypes vary between ancestral groups, underscoring the importance of multi-ancestral approaches to genetic studies in SLE and other autoimmune/inflammatory diseases.http://www.sciencedirect.com/science/article/pii/S2589909025000036LupusGeneticJuvenile-onsetSLEHLAHaplotype |
| spellingShingle | Yves Renaudineau Amandine Charras Valentina Natoli Nicolas Congy-Jolivet Sam Haldenby Xuan Liu Yongxiang Fang Eve MD. Smith Michael W. Beresford Christian M. Hedrich Carla Roberts Eslam Al-Abadi Kate Armon Kathryn Bailey Coziana Ciurtin Janet Gardner-Medwin Kirsty Haslam Daniel P. Hawley Alice Leahy Valentina Leone Flora McErlane Gita Modgil Clarissa Pilkington Athimalaipet V. Ramanan Satyapal Rangaraj Phil Riley Arani Sridhar Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels Journal of Translational Autoimmunity Lupus Genetic Juvenile-onset SLE HLA Haplotype |
| title | Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels |
| title_full | Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels |
| title_fullStr | Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels |
| title_full_unstemmed | Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels |
| title_short | Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels |
| title_sort | across ancestries hla b∗08 01∼drb1∗03 01 dr3 and hla dqa∗01 02 dr2 increase the risk to develop juvenile onset systemic lupus erythematosus through low complement c4 levels |
| topic | Lupus Genetic Juvenile-onset SLE HLA Haplotype |
| url | http://www.sciencedirect.com/science/article/pii/S2589909025000036 |
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