Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes.
autoantibodies
genetic
immune complex diseases
polymorphism
systemic sclerosis
Journal
Annals of the rheumatic diseases
ISSN: 1468-2060
Titre abrégé: Ann Rheum Dis
Pays: England
ID NLM: 0372355
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
11
01
2021
revised:
04
03
2021
accepted:
08
03
2021
pubmed:
8
6
2021
medline:
28
6
2022
entrez:
7
6
2021
Statut:
ppublish
Résumé
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. 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). 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 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.
Identifiants
pubmed: 34096881
pii: annrheumdis-2021-219884
doi: 10.1136/annrheumdis-2021-219884
pmc: PMC8292594
doi:
Substances chimiques
HLA-DRB1 Chains
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1040-1047Subventions
Organisme : Wellcome Trust
ID : 207491/Z/17/Z
Pays : United Kingdom
Organisme : NIAMS NIH HHS
ID : R01 AR073284
Pays : United States
Organisme : Versus Arthritis
ID : 21754
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Investigateurs
P Carreira
(P)
I Castellvi
(I)
R Ríos
(R)
J L Callejas
(JL)
R García Portales
(R)
A Fernández-Nebro
(A)
F J García-Hernández
(FJ)
M A Aguirre
(MA)
B Fernández-Gutiérrez
(B)
L Rodríguez-Rodríguez
(L)
P García de la Peña
(P)
E Vicente
(E)
J L Andreu
(JL)
M Fernández de Castro
(M)
F J López-Longo
(FJ)
V Fonollosa
(V)
A Guillén
(A)
G Espinosa
(G)
C Tolosa
(C)
A Pros
(A)
E Beltrán
(E)
M Rodríguez Carballeira
(M)
F J Narváez
(FJ)
M Rubio Rivas
(M)
V Ortiz-Santamaría
(V)
A B Madroñero
(AB)
M A González-Gay
(MA)
B Díaz
(B)
L Trapiella
(L)
M V Egurbide
(MV)
P Fanlo-Mateo
(P)
L Saez-Comet
(L)
F Díaz
(F)
J A Roman-Ivorra
(JA)
J J Alegre Sancho
(JJ)
M Freire
(M)
F J Blanco Garcia
(FJ)
N Oreiro
(N)
T Witte
(T)
A Kreuter
(A)
G Riemekasten
(G)
P Airo
(P)
C Magro
(C)
A E Voskuyl
(AE)
M C Vonk
(MC)
R Hesselstrand
(R)
A Nordin
(A)
C Lunardi
(C)
A Gabrielli
(A)
A Hoffmann-Vold
(A)
J H W Distler
(JHW)
L Padyukov
(L)
B Koeleman
(B)
W Stevens
(W)
M Nikpour
(M)
J Zochling
(J)
J Sahhar
(J)
J Roddy
(J)
P Nash
(P)
K Tymms
(K)
M Rischmueller
(M)
S Lester
(S)
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.