TY - JOUR T1 - Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis DO - 10.1136/annrheumdis-2021-219884 SP - annrheumdis-2021-219884 AU - Marialbert Acosta-Herrera AU - Martin Kerick AU - Elena Lopéz-Isac AU - Shervin Assassi AU - Lorenzo Beretta AU - Carmen Pilar Simeón-Aznar AU - Norberto Ortego-Centeno AU - International SSc Group AU - Susanna M Proudman AU - Australian Scleroderma Interest Group (ASIG) AU - Nicolas Hunzelmann AU - Gianluca Moroncini AU - Jeska K de Vries-Bouwstra AU - Gisela Orozco AU - Anne Barton AU - Ariane L Herrick AU - Chikashi Terao AU - Yannick Allanore AU - Matthew A Brown AU - Timothy RDJ Radstake AU - Carmen Fonseca AU - Christopher P Denton AU - Maureen D Mayes AU - Javier Martin Y1 - 2021/03/31 UR - http://ard.bmj.com/content/early/2021/03/31/annrheumdis-2021-219884.abstract N2 - 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.Summary statistics are available from the corresponding author upon reasonable request. ER -