Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes
| Autor: | Acosta-Herrera, Marialbert, Kerick, Martin, Lopéz-Isac, Elena, Assassi, Shervin, Beretta, Lorenzo, Simeón-Aznar, Carmen Pilar, Ortego-Centeno, Norberto, International SSc Group, Proudman, Susanna M, Australian Scleroderma Interest Group (ASIG), Hunzelmann, Nicolas, Moroncini, Gianluca, de Vries-Bouwstra, Jeska K, Orozco, Gisela, Barton, Anne, Herrick, Ariane L, Terao, Chikashi, Allanore, Yannick, Brown, Matthew A, Radstake, Timothy Rdj, Fonseca, Carmen, Denton, Christopher P, Mayes, Maureen D, Martin, Javier |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, National Institutes of Health (US), Manchester Biomedical Research Centre, Universidad de Cantabria, Institut Català de la Salut, [Acosta-Herrera M, Kerick M, Lopéz-Isac E] Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain. [Assassi S] Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA. [Beretta L] Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy. [Simeón-Aznar CP] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
autoantibodies systemic sclerosis Immunology Locus (genetics) Single-nucleotide polymorphism Human leukocyte antigen Major histocompatibility complex General Biochemistry Genetics and Molecular Biology polymorphism Major Histocompatibility Complex 03 medical and health sciences 0302 clinical medicine Antígens HLA Rheumatology Polymorphism (computer science) Other subheadings::Other subheadings::/immunology [Other subheadings] Immunology and Allergy Medicine Humans Genetic Predisposition to Disease Otros calificadores::Otros calificadores::/inmunología [Otros calificadores] Allele skin and connective tissue diseases Alleles 030203 arthritis & rheumatology Skin and Connective Tissue Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Scleroderma Systemic [DISEASES] Scleroderma Systemic Amino Acids Peptides and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Histocompatibility Antigens Class II [CHEMICALS AND DRUGS] biology immune complex diseases business.industry enfermedades de la piel y tejido conjuntivo::enfermedades de la piel y tejido conjuntivo::enfermedades de la piel::esclerodermia sistémica [ENFERMEDADES] Autoantibody 030104 developmental biology biology.protein Esclerosi sistemàtica progressiva genetic Immunogenètica business Immune complex disease aminoácidos péptidos y proteínas::proteínas::glicoproteínas::glicoproteínas de membranas::antígenos de histocompatibilidad de clase II [COMPUESTOS QUÍMICOS Y DROGAS] Genome-Wide Association Study HLA-DRB1 Chains |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Annals of the Rheumatic Diseases Annals of the Rheumatic Diseases, 80(8), 1040-1047. BMJ PUBLISHING GROUP Ann Rheum Dis . 2021 Apr 1;80(8):1040-1047 UCrea Repositorio Abierto de la Universidad de Cantabria Universidad de Cantabria (UC) Scientia |
| Popis: | Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression. This work was supported by the Spanish Ministry of Science and Innovation (grant ref. SAF2015-66761-P and RTI20181013 (32-B-100)), Red de Investigación en Inflamación y Enfermedades Reumáticas from Instituto de Salud Carlos III (RD16/0012/0013) and grants from National Institutes of Health (R01AR073284) and DoD (W81XWH-16-1-0296). MAH was funded by the Spanish Ministry of Science and Innovation through the Juan de la Cierva Incorporacion program (ref. IJC2018-035131-I). GO, AB and ALH were supported by the NIHR Manchester Biomedical Research Centre and Versus Arthritis (grant ref 21754) |
| Databáze: | OpenAIRE |
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