A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

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Publication year
2015Author(s)
Source
Annals of the Rheumatic Diseases, 74, 3, (2015), pp. e15ISSN
Publication type
Article / Letter to editor

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Organization
Human Genetics
Psychiatry
Health Evidence
Rheumatology
IQ Healthcare
Journal title
Annals of the Rheumatic Diseases
Volume
vol. 74
Issue
iss. 3
Page start
p. e15
Page end
p. e15
Subject
Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 18: Healthcare improvement science RIHS: Radboud Institute for Health Sciences; Radboudumc 5: Inflammatory diseases RIHS: Radboud Institute for Health Sciences; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical NeuroscienceAbstract
Introduction Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. Methods We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. Results The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. Conclusions Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.
This item appears in the following Collection(s)
- Academic publications [202914]
- Electronic publications [101091]
- Faculty of Medical Sciences [80065]
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