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

被引：29

作者：

Acosta-Herrera, Marialbert ^{[1
]}

Kerick, Martin ^{[1
]}

Lopez-Isac, Elena ^{[1
]}

Assassi, Shervin ^{[2
]}

Beretta, Lorenzo ^{[3
]}

Simeon-Aznar, Carmen Pilar ^{[4
]}

Ortego-Centeno, Norberto ^{[5
]}

Proudman, Susanna M. ^{[6
]}

Hunzelmann, Nicolas ^{[7
]}

Moroncini, Gianluca ^{[8
]}

de Vries-Bouwstra, Jeska K. ^{[9
]}

Orozco, Gisela ^{[10
,11
]}

Barton, Anne ^{[10
,11
]}

Herrick, Ariane L. ^{[12
]}

Terao, Chikashi ^{[13
]}

Allanore, Yannick ^{[14
]}

Brown, Matthew A. ^{[15
,16
]}

Radstake, Timothy R. D. J. ^{[17
]}

Fonseca, Carmen ^{[18
]}

Denton, Christopher P. ^{[18
]}

Mayes, Maureen D. ^{[2
]}

Martin, Javier ^{[1
]}

机构：

[1] CSIC, Inst Parasitol & Biomed Lopez Neyra, Dept Cell Biol & Immunol, Granada, Andalucia, Spain

[2] Univ Texas Hlth Sci Ctr Houston, Rheumatol & Clin Immunogenet, Houston, TX 77030 USA

[3] Fdn IRCCS Ca Granda Osped Maggiore Policlin Milan, Referral Ctr Syst Autoimmune Dis, Milan, Italy

[4] Valle de Hebron Hosp, Dept Internal Med, Barcelona, Spain

[5] Clin Univ Hosp, Dept Internal Med, Granada, Spain

[6] Royal Adelaide Hosp, Dept Rheumatol, Victoria, Australia

[7] Univ Cologne, Dept Dermatol, Cologne, Germany

[8] Univ Politecn Marche & Ospedali Riuniti, Dept Clin & Mol Sci, Ancona, Italy

[9] Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands

[10] Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Ctr Genet & Genom Versus Arthrit,Div Musculoskele, Manchester, England

[11] Manchester Univ NHS Fdn Trust, NIHR Manchester Biomed Res Ctr, Manchester, England

[12] Univ Manchester, Salford Royal NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Div Musculoskeletal & Dermatol Sci, Manchester, England

[13] RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet, Yokohama, Kanagawa, Japan

[14] Hosp Cochin, Dept Rheumatol A, Paris, Ile De France, France

[15] Guys & St Thomas NHS Fdn Trust, NIHR Biomed Res Ctr, London, England

[16] Kings Coll London, London, England

[17] Univ Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands

[18] Royal Free & Univ Coll Med Sch, Ctr Rheumatol, London, England

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2021年 / 80卷 / 08期

基金：

美国国家卫生研究院;

关键词：

systemic sclerosis; autoantibodies; immune complex diseases; polymorphism; genetic; RISK LOCI; CLASSIFICATION; GENES; GWAS; MHC; IMMUNOGENETICS; PATHOGENESIS; VARIANTS; GENETICS; CRITERIA;

D O I：

10.1136/annrheumdis-2021-219884

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1040 / 1047

页数：8

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