Association between radiographic severity of rheumatoid arthritis and shared epitope alleles: differing mechanisms of susceptibility and protection

Mewar, Devesh; Marinou, Ioanna; Coote, Annabel; Moore, David; Akil, Mohammed; Smillie, David; Dickson, Marion C.; Binks, Michael; Montgomery, Douglas S.; Wilson, Anthony G.

doi:10.1136/ard.2007.075382

Cited by 32 publications

(30 citation statements)

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“…[39][40][41] This is of interest in light of suggestions that *04-SE alleles are associated with rapidly progressive periodontal disease. 42 Our finding that HLA-DRB1*0401 is more strongly associated with ACPA-positive RA than HLADRB1*0404 is consistent with most previous reports, 10,[43][44][45] although not all. 46 Subtle differences with other reports of a hierarchy of risk (*044*104*01) 47 may be attributed to differences in the genetic or environmental background, and/or to differences in statistical methods.…”

Section: Discussionsupporting

confidence: 91%

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

et al. 2011

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Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. 70 DERAA 74 , D 70 and I 67 protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1*0401B*04044*0101B*1001 (*04044*0101: P ¼ 0.0003). HLA-DRB1*0401/*0404 compound heterozygosity conferred a risk similar to *0401 homozygosity (P ¼ 0.70). Protective effects of D 70 and I 67 were similar. Predictions of the D 70 model fitted the data better than those of the I 67 model. The protective effect of D 70 showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P ¼ 5.8 Â 10 À4 ), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P ¼ 0.0012).In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D 70 specifically protected against antibody-positive RA.

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Section: Discussionsupporting

confidence: 91%

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

et al. 2011

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“…This suggests that the protection afforded by DERAA does not simply counteract the mechanisms used by SE alleles, which appear to associate with severity through the production of antibodies to citrullinated antigens (32,33). A similar lack of protection of DERAA alleles against RAassociated antibodies in established RA was recently reported (34). Third, the protective influence of DE-RAA alleles did not imply clinically milder disease at study inclusion or spontaneous remission over time.…”

Section: Discussionsupporting

confidence: 52%

The DERAA HLA–DR alleles in patients with early polyarthritis: Protection against severe disease and lack of association with rheumatoid arthritis autoantibodies

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Cossette²,

Chartier³

et al. 2009

Arthritis & Rheumatism

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Objective. To define the association of alleles encoding the HLA-DR rheumatoid arthritis (RA) protective epitope (DERAA) with the presence of RAassociated antibodies at study inclusion and with severe outcome in patients with early polyarthritis (EPA).Methods. Consecutive EPA patients (n ‫؍‬ 210) were evaluated early (mean of 4.8 months after diagnosis) and prospectively (for 30 months). HLA class II typing was performed by polymerase chain reaction using sequence-specific primers, and HLA-DR alleles DERAA, RA-associated shared epitope (SE), and non-SE/non-DERAA (neither SE nor DERAA) were identified. RA-associated antibodies identified were anti-Sa/ citrullinated vimentin, anti-cyclic citrullinated peptide 2, and IgM rheumatoid factor. Severe disease was defined according to a preset threshold of joint destruction and/or functional limitation.Results. DERAA and SE alleles were present in 62 and 110 of the 210 EPA patients, respectively. At 30 months, severe disease was present in 78 patients (37%). In contrast to SE alleles, DERAA alleles were not associated with the production of RA-associated antibodies, but were strongly protective against severe disease at 30 months (odds ratio 0.30, P < 0.001). DERAA alleles emerged as a strong, independent protective marker on multivariate analysis. The protective effect of DERAA was seen only in patients who did not already have erosions at study inclusion, was independent of the presence of antibodies, but was not associated with spontaneous remission.Conclusion. In our EPA cohort, the presence of a DERAA sequence was a strong independent predictor of a better prognosis, but only in the absence of erosive disease that was already present at inclusion. Identification of DERAA alleles may help in managing the large subgroup of EPA patients who do not have erosions at baseline.

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“…The SE motif consists of three homologous amino acid sequence variants: (1) QKRAA, the SE variant that is the most common motif among Caucasian, is coded primarily by the HLA-DRB1*0401 allele, (2) the second most common motif, QRRAA, is coded by several alleles, among them HLA-DRB1*0404, HLA-DRB1*0101 and HLA-DRB1*0405 and (3) the third motif, RRRAA, coded by allele HLA-DRB1*1001, is the rarest. In addition to increasing RA risk, SE-coding HLA-DRB1 alleles have been shown to associate with more severe disease and to exhibit allele-dose effect, that is patients with two SE-coding alleles tend to experience more severe disease than patients with one allele, who, in turn, have more severe RA than SE-negative patients [158,159].…”

Section: Hla and Autoimmune Diseasesmentioning

confidence: 99%

Clinical Role of Human Leukocyte Antigen in Health and Disease

2015

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Most of the genes in the major histocompatibility complex (MHC) region express high polymorphism that is fundamental for their function. The most important function of human leukocyte antigen (HLA) molecule is in the induction, regulation of immune responses and the selection of the T cell repertoire. A clinician's attention is normally drawn to a system only when it malfunctions. The HLA system is no exception in this regard, but in contrast to other systems, it also arouses interest when it functions well -too well, in fact. Population studies carried out over the last several decades have identified a long list of human diseases that are significantly more common among individuals that carry particular HLA alleles including inflammatory, autoimmune and malignant disorders. HLAdisease association is the name of this phenomenon, and the mechanism underlying is still a subject of hot debate. Social behaviours are affected by HLA genes and preference for HLA disparate mates may provide 'good genes' for an individual's offspring. Also, certain HLA genes may be associated with shorter life and others with longer lifespan, but the effects depend both on the genetic background and on the environmental conditions. The following is a general overview of the important functional aspects of HLA in health and diseases.

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Association between radiographic severity of rheumatoid arthritis and shared epitope alleles: differing mechanisms of susceptibility and protection

Abstract: These data suggest that multiple biological mechanisms underlie the DRB1 association with rheumatoid arthritis severity.

Cited by 32 publications

References 13 publications

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

The DERAA HLA–DR alleles in patients with early polyarthritis: Protection against severe disease and lack of association with rheumatoid arthritis autoantibodies

Clinical Role of Human Leukocyte Antigen in Health and Disease

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