Universität zu Köln

Acosta-Herrera, Marialbert ORCID: 0000-0002-9868-6535, Kerick, Martin ORCID: 0000-0002-6298-4514, Lopez-Isac, Elena, Assassi, Shervin, Beretta, Lorenzo, Simeon-Aznar, Carmen Pilar, Ortego-Centeno, Norberto, Proudman, Susanna M., Hunzelmann, Nicolas, Moroncini, Gianluca, de Vries-Bouwstra, Jeska K., Orozco, Gisela ORCID: 0000-0002-3479-0448, Barton, Anne, Herrick, Ariane L., Terao, Chikashi, Allanore, Yannick, Brown, Matthew A., Radstake, Timothy R. D. J., Fonseca, Carmen, Denton, Christopher P., Mayes, Maureen D. and Martin, Javier ORCID: 0000-0002-2202-0622 (2021). Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes. Ann. Rheum. Dis., 80 (8). S. 1040 - 1048. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-2060

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Acosta-Herrera, Marialbert UNSPECIFIED orcid.org/0000-0002-9868-6535 UNSPECIFIED Kerick, Martin UNSPECIFIED orcid.org/0000-0002-6298-4514 UNSPECIFIED Lopez-Isac, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Assassi, Shervin UNSPECIFIED UNSPECIFIED UNSPECIFIED Beretta, Lorenzo UNSPECIFIED UNSPECIFIED UNSPECIFIED Simeon-Aznar, Carmen Pilar UNSPECIFIED UNSPECIFIED UNSPECIFIED Ortego-Centeno, Norberto UNSPECIFIED UNSPECIFIED UNSPECIFIED Proudman, Susanna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hunzelmann, Nicolas UNSPECIFIED UNSPECIFIED UNSPECIFIED Moroncini, Gianluca UNSPECIFIED UNSPECIFIED UNSPECIFIED de Vries-Bouwstra, Jeska K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Orozco, Gisela UNSPECIFIED orcid.org/0000-0002-3479-0448 UNSPECIFIED Barton, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrick, Ariane L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Terao, Chikashi UNSPECIFIED UNSPECIFIED UNSPECIFIED Allanore, Yannick UNSPECIFIED UNSPECIFIED UNSPECIFIED Brown, Matthew A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Radstake, Timothy R. D. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fonseca, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Denton, Christopher P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayes, Maureen D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martin, Javier UNSPECIFIED orcid.org/0000-0002-2202-0622 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-605449
DOI:	10.1136/annrheumdis-2021-219884
Journal or Publication Title:	Ann. Rheum. Dis.
Volume:	80
Number:	8
Page Range:	S. 1040 - 1048
Date:	2021
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1468-2060
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RISK LOCI; CLASSIFICATION; GENES; GWAS; MHC; IMMUNOGENETICS; PATHOGENESIS; VARIANTS; GENETICS; CRITERIA Multiple languages Rheumatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60544