Interaction of HLA-DRB1*09:01 and *04:05 with Smoking Suggests Distinctive Mechanisms of Rheumatoid Arthritis Susceptibility Beyond the Shared Epitope

Objective.Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or -negative RA.Methods.All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression.Results.SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46–0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01.Conclusion.HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.

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Association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope and smoking status in Brazilian patients with rheumatoid arthritis

Clinics ◽

10.1590/s1807-59322011000800016 ◽

2011 ◽

Vol 66 (8) ◽

pp. 1401-1406 ◽

Cited By ~ 8

Author(s):

Michel Alexandre Yazbek ◽

Silvia de Barros-Mazon ◽

Cláudio Lúcio Rossi ◽

Ana Carolina Londe ◽

Lilian Tereza Lavras Costallat ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Association Analysis ◽

Shared Epitope ◽

Smoking Status ◽

Nuclear Antigen ◽

Cyclic Citrullinated Peptide ◽

Epstein Barr ◽

Citrullinated Peptide ◽

Epstein Barr Nuclear Antigen ◽

Peptide Antibodies

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Antibodies toPorphyromonas gingivalisAre Associated with Anticitrullinated Protein Antibodies in Patients with Rheumatoid Arthritis and Their Relatives

The Journal of Rheumatology ◽

10.3899/jrheum.091323 ◽

2010 ◽

Vol 37 (6) ◽

pp. 1105-1112 ◽

Cited By ~ 144

Author(s):

CAROL A. HITCHON ◽

FATIHA CHANDAD ◽

ELIZABETH D. FERUCCI ◽

ANNEMIEK WILLEMZE ◽

ANDREEA IOAN-FACSINAY ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Responses ◽

Rheumatoid Factor ◽

Porphyromonas Gingivalis ◽

Immune Tolerance ◽

Oral Hygiene ◽

Shared Epitope ◽

Poor Oral Hygiene ◽

Citrullinated Peptide ◽

Anticitrullinated Protein Antibodies

Objective.Anticitrullinated protein antibodies (ACPA) are relatively specific for rheumatoid arthritis (RA), and predate disease. The oral pathogenPorphyromonas gingivalismay play a role in breaking immune tolerance to citrullinated antigens. We studied a cohort of patients with RA and their relatives looking for associations between anti-P. gingivalisantibodies and ACPA.Methods.Patients with RA (n = 82) and their relatives (n = 205) from a North American Native (NAN) population were studied, along with 47 NAN and 60 non-NAN controls. IgM and IgA rheumatoid factor (RF) were tested by nephelometry and ELISA. Second-generation anticyclic citrullinated peptide (anti-CCP2) isotypes and IgG anti-P. gingivalislipopolysaccharides were tested by ELISA. HLA-DRB1 typing was performed by sequencing. Oral hygiene and smoking habits were assessed by questionnaires.Results.Autoantibody frequency in patients with RA and relatives: ACPA 91% vs 19%, respectively; IgM RF 82% vs 17%; IgA RF 48% vs 22%. Anti-P. gingivalislevels were higher in patients with RA compared to relatives and controls (p = 0.005) and higher in ACPA-positive patients with RA than in ACPA-negative patients with RA (p = 0.04) and relatives (p < 0.001), but comparable in RF-positive and RF-negative patients and relatives. Poor oral hygiene and smoking were prevalent, but with no clear association with autoantibodies. Relatives with 2 shared-epitope alleles were more likely to be ACPA-positive (OR 2.5, p = 0.02).Conclusion.In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalisantibodies were associated with ACPA. These findings suggest that immune responses toP. gingivalismay be involved in breaking immune tolerance to citrullinated antigens.

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Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: Contrasting effects of HLA-DR3 and the shared epitope alleles

Arthritis & Rheumatism ◽

10.1002/art.21419 ◽

2005 ◽

Vol 52 (12) ◽

pp. 3813-3818 ◽

Cited By ~ 145

Author(s):

Patricia Irigoyen ◽

Annette T. Lee ◽

Mark H. Wener ◽

Wentian Li ◽

Marlena Kern ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Shared Epitope ◽

Cyclic Citrullinated Peptide ◽

Hla Dr3 ◽

Citrullinated Peptide ◽

Peptide Antibodies

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Antihomocitrullinated Fibrinogen Antibodies are Specific to Rheumatoid Arthritis and Frequently Bind Citrullinated Proteins/peptides

The Journal of Rheumatology ◽

10.3899/jrheum.130742 ◽

2014 ◽

Vol 41 (2) ◽

pp. 270-279 ◽

Cited By ~ 51

Author(s):

Mathias Scinocca ◽

David A. Bell ◽

Maud Racapé ◽

Radha Joseph ◽

Gary Shaw ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mass Spectrometry ◽

Computer Modeling ◽

Lupus Erythematosus ◽

Shared Epitope ◽

Affinity Purification ◽

Peptide Antibody ◽

Citrullinated Proteins ◽

Peptide Interaction ◽

Citrullinated Peptide

Objective.Anticitrullinated protein/peptide antibodies (ACPA) are implicated in rheumatoid arthritis (RA) pathogenesis and linked to the shared epitope (SE). Citrulline modification is very similar to a different modified amino acid, homocitrulline. We investigated antihomocitrullinated protein/ peptide antibody (AHCPA) specificity for RA, whether ACPA were also able to bind homocitrullinated targets, and whether the SE could accommodate homocitrullinated peptide.Methods.Homocitrullinated fibrinogen was used to screen sera from patients with RA, psoriatic arthritis, and systemic lupus erythematosus, and healthy subjects for AHCPA using ELISA. Homocitrullination sites on fibrinogen were identified by mass spectrometry. ACPA were affinity-purified using a synthetic citrullinated peptide and tested for binding to homocitrullinated protein/peptide. Inhibition of antihomocitrullinated fibrinogen antibody binding was examined. Homocitrullinated peptide interaction with the SE was studied using computer modeling.Results.IgG antihomocitrullinated fibrinogen antibodies were found specifically in 49% of patients with RA. Enrichment of ACPA by affinity purification from 5 patients with RA also enriched AHCPA. Serum AHCPA was inhibited by citrullinated fibrinogen and more significantly by homocitrullinated fibrinogen. Computer modeling indicated that the SE could accommodate a homocitrullinated peptide without steric hindrance. Mass spectrometry identified that 89/103 lysines of fibrinogen could be homocitrullinated, and 5 peptides that could be both citrullinated and homocitrullinated and are predicted to bind the SE.Conclusion.Antihomocitrullinated fibrinogen antibodies are specific to RA. The presence of AHCPA coincides with ACPA, and AHCPA copurifies with ACPA in affinity purification and is inhibited by citrullinated and homocitrullinated antigens. Thus AHCPA and ACPA are frequently cross-reactive and homocitrullinated proteins/peptides may bind the SE.

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The association between the HLA-DRB1 shared epitope alleles and the risk of rheumatoid arthritis is influenced by massive gene-gene interactions

10.1101/221416 ◽

2017 ◽

Author(s):

Lina-Marcela Diaz-Gallo ◽

Daniel Ramsköld ◽

Klementy Shchetynsky ◽

Lasse Folkersen ◽

Karine Chemin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Shared Epitope ◽

Disease Risk ◽

Gene Interactions ◽

Additive Interaction ◽

The North ◽

Risk Alleles ◽

Genome Wide ◽

Kolmogorov Smirnov ◽

Citrullinated Protein

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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TMEM187-IRAK1Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin

Journal of Immunology Research ◽

10.1155/2017/4915950 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Olfa Khalifa ◽

Nathalie Balandraud ◽

Nathalie Lambert ◽

Isabelle Auger ◽

Jean Roudier ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Protective Effect ◽

Meta Analysis ◽

Geographic Origin ◽

Significant Risk ◽

Tunisian Population ◽

French Population ◽

Major Allele ◽

First Time ◽

Arthritis Susceptibility

Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containingTMEM187andIRAK1(rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n=408) compared with age-matched controls (n=471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated withTMEM187-IRAK1polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations.

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