Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Marialbert Acosta-Herrera; Martin Kerick; Elena Lopéz-Isac; Shervin Assassi; Lorenzo Beretta; Carmen Pilar Simeón-Aznar; Norberto Ortego-Centeno; International SSc Group; Susanna M Proudman; Australian Scleroderma Interest Group (ASIG); Nicolas Hunzelmann; Gianluca Moroncini; Jeska K de Vries-Bouwstra; Gisela Orozco; Anne Barton; Ariane L Herrick; Chikashi Terao; Yannick Allanore; Matthew A Brown; Timothy Rdj Radstake; Carmen Fonseca; Christopher P Denton; Maureen D Mayes; Javier Martin

doi:10.1136/annrheumdis-2021-219884

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Ann Rheum Dis. 2021 Aug;80(8):1040-1047. doi: 10.1136/annrheumdis-2021-219884. Epub 2021 Apr 1.

Authors

Marialbert Acosta-Herrera¹, Martin Kerick², Elena Lopéz-Isac², Shervin Assassi³, Lorenzo Beretta⁴, Carmen Pilar Simeón-Aznar⁵, Norberto Ortego-Centeno⁶; International SSc Group; Susanna M Proudman⁷; Australian Scleroderma Interest Group (ASIG); Nicolas Hunzelmann⁸, Gianluca Moroncini⁹, Jeska K de Vries-Bouwstra¹⁰, Gisela Orozco^{11

12}, Anne Barton^{11

12}, Ariane L Herrick¹³, Chikashi Terao¹⁴, Yannick Allanore¹⁵, Matthew A Brown¹⁶, Timothy Rdj Radstake¹⁷, Carmen Fonseca¹⁸, Christopher P Denton¹⁸, Maureen D Mayes³, Javier Martin²

Collaborators

P Carreira, I Castellvi, R Ríos, J L Callejas, R García Portales, A Fernández-Nebro, F J García-Hernández, M A Aguirre, B Fernández-Gutiérrez, L Rodríguez-Rodríguez, P García de la Peña, E Vicente, J L Andreu, M Fernández de Castro, F J López-Longo, V Fonollosa, A Guillén, G Espinosa, C Tolosa, A Pros, E Beltrán, M Rodríguez Carballeira, F J Narváez, M Rubio Rivas, V Ortiz-Santamaría, A B Madroñero, M A González-Gay, B Díaz, L Trapiella, M V Egurbide, P Fanlo-Mateo, L Saez-Comet, F Díaz, J A Roman-Ivorra, J J Alegre Sancho, M Freire, F J Blanco Garcia, N Oreiro, T Witte, A Kreuter, G Riemekasten, P Airo, C Magro, A E Voskuyl, M C Vonk, R Hesselstrand, A Nordin, C Lunardi, A Gabrielli, A Hoffmann-Vold, J H W Distler, L Padyukov, B Koeleman, W Stevens, M Nikpour, J Zochling, J Sahhar, J Roddy, P Nash, K Tymms, M Rischmueller, S Lester

Affiliations

¹ Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain m.acostaherrera@ipb.csic.es.
² Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain.
³ Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁴ Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
⁵ Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain.
⁶ Department of Internal Medicine, Clinic University Hospital, Granada, Spain.
⁷ Department of Rheumatology, Royal Adelaide Hospital, Adelaide, Victoria, Australia.
⁸ Department of Dermatology, University of Cologne, Cologne, Germany.
⁹ Department of Clinical and Molecular Science, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
¹⁰ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
¹¹ Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
¹² NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.
¹³ Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
¹⁴ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
¹⁵ Department of Rheumatology A, Hospital Cochin, Paris, Île-de-France, France.
¹⁶ NIHR Biomedical Research Centre, Guy's and Saint Thomas' NHS Foundation Trust and King's College, London, UK.
¹⁷ Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁸ Centre for Rheumatology, Royal Free and University College Medical School, London, UK.

Abstract

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.

Keywords: autoantibodies; genetic; immune complex diseases; polymorphism; systemic sclerosis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Alleles
Genetic Predisposition to Disease
Genome-Wide Association Study*
HLA-DRB1 Chains / genetics
Humans
Major Histocompatibility Complex
Scleroderma, Systemic* / genetics

Substances

HLA-DRB1 Chains

Abstract

Publication types

MeSH terms

Substances

Grants and funding