Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis

AbstractIn anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope alleles (SE), is the highest genetic risk factor. Here, we aimed to investigate whether gene-gene interactions influence this HLA-DRB1 related major disease risk; specifically, we set out to test if non-HLA SNPs, conferring low diseases risk on their own, can modulate the HLA-DRB1 SE effect to develop ACPA-positive RA.To address this question, we computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish EIRA and the North American NARAC. We found a strong enrichment of significant interactions (AP p-values<0.05) between the HLA-DRB1 SE alleles and a group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov [KS] test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 201 out of 1,492 SNPs in consistent interaction for both cohorts, were eQTLs in SE alleles context in PBMCs from ACPA-positive RA patients. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after discounting the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581, AP FDR corrected p <0.05).Our data demonstrate that the association between the HLA-DRB1 SE alleles and the risk of ACPA-positive RA is modulated by massive genetic interactions with non-HLA genetic variants.

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Association Between STAT4 rs7574865 Polymorphism and Rheumatoid Arthritis: Debate Unresolved

The Open Rheumatology Journal ◽

10.2174/1874312901812010172 ◽

2018 ◽

Vol 12 (1) ◽

pp. 172-178

Author(s):

Iman Tarakji ◽

Wafa Habbal ◽

Fawza Monem

Keyword(s):

Rheumatoid Arthritis ◽

Genetic Factors ◽

Shared Epitope ◽

Direct Sequencing ◽

Healthy Controls ◽

Asian Populations ◽

Genotype Frequencies ◽

Potential Impact ◽

Acpa Status ◽

Citrullinated Protein

Background: STAT4 rs7574865 polymorphism has been evidently associated with susceptibility to Rheumatoid Arthritis (RA) in European and Eastern Asian populations, whereas studies in other countries reported otherwise. Objective: We investigated the distribution of STAT4 rs7574865 polymorphism in a group of Syrian RA patients. Methods: Eighty-one RA patients and forty healthy controls were enrolled and STAT4 rs7574865 was genotyped by direct sequencing. RA patients were stratified according to Anti-Citrullinated Protein Antibodies (ACPA) status for analysis. Results: Minor T allele frequencies were 30.4%, 16.7%, and 23.8% in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively. No significant differences in STAT4 rs7574865 allele/genotype frequencies were found between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05). Conclusion: STAT4 rs7574865 TT genotype showed a potential impact on ACPA positivity in Syrian RA patients. However, STAT4 rs7574865 effect on RA onset and severity is minor compared to other genetic factors such as HLA-DRB1 shared epitope alleles.

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AB0334 Very high titer of anti-citrullinated protein antibodies is associated with the achievement of clinical remission by abatacept in biologic-naïve patients with rheumatoid arthritis (the abroad study)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-eular.2656 ◽

2013 ◽

Vol 72 (Suppl 3) ◽

pp. A889.2-A889 ◽

Cited By ~ 1

Author(s):

T. Fujii ◽

M. Sekiguchi ◽

K. Matsui ◽

M. Kitano ◽

M. Hashimoto ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Remission ◽

High Titer ◽

Citrullinated Protein ◽

Very High

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New classification of the shared epitope in rheumatoid arthritis: impact on the production of various anti-citrullinated protein antibodies

Rheumatology ◽

10.1093/rheumatology/kep338 ◽

2009 ◽

Vol 49 (1) ◽

pp. 25-33 ◽

Cited By ~ 22

Author(s):

Ágnes Gyetvai ◽

Zoltán Szekanecz ◽

Lilla Soós ◽

Zoltán Szabó ◽

Andrea Fekete ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Shared Epitope ◽

New Classification ◽

Citrullinated Protein

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Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.091355 ◽

2008 ◽

Vol 68 (5) ◽

pp. 736-743 ◽

Cited By ~ 125

Author(s):

O Snir ◽

M Widhe ◽

C von Spee ◽

J Lindberg ◽

L Padyukov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Shared Epitope ◽

Type Ii Collagen ◽

Cross Reactivity ◽

Igg Antibodies ◽

Serum Samples ◽

Hla Dr ◽

Citrullinated Proteins ◽

The Relationship ◽

Citrullinated Protein

Background:Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles.Objective:To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles.Methods:Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, α-enolase peptide-1 and the C1-epitope of type II collagen (C1III). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed.Results:72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients’ sera and in 41% for both citrullinated α-enolase peptide-1 and citrullinated C1III. These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles.Conclusions:Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

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