Differential associations of HLA‐DR antigens with rheumatoid arthritis (RA) in Basques: High frequency of DR1 and DR10 and lack of association with HLA‐DR4 or any of its subtypes

Objective. To determine whether the tumor necrosis factor ␣ (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA).Methods. The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score.Results. Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n ‫؍‬ 49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n ‫؍‬ 140). Presence of the SE (n ‫؍‬ 137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n ‫؍‬ 52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequili-

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confidence: 99%

Association of tumor necrosis factor α polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

Khanna

Park

et al. 2006

“…HLA-DR4 is associated with RA in populations of Northern European ancestry (1)(2)(3). Among Greeks, Spaniards, Israeli Jews, and African blacks, RA is associated with DR1 and DR10 (4)(5)(6)(7)(8), while among North American Natives, the RA-linked marker is DR14 (9,10). DNA sequencing has shown that RA-associated alleles share certain amino acid sequences between positions 70 and 74 in the third hypervariable region of DRB1 (11,12).…”

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confidence: 99%

HLA-DRB1 alleles associated with susceptibility or resistance to rheumatoid arthritis, articular deformities, and disability in Mexican Americans

Rincón

Escalante

1999

“…This sequence may be encoded by certain HLA-DR4 (DRB1*04) or non-DR4 alleles; thus, the concept of a "shared epitope" or "rheumatoid epitope" has emerged (1)(2)(3)(4). A gene-dose effect has been suggested for RA, in which individuals homozygous for HLADRB1*0401 and those homozygous for the rheumatoid epitope exhibit more severe and destructive disease, particularly extraarticular manifestations, than those who are heterozygous or lack the rheumatoid epitope (5-7).…”

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confidence: 99%

HLA—DRB1 genes and disease severity in rheumatoid arthritis

Reveille

Alarcón

Fowler

et al. 1996

Objective. To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated In the minocycline in RA (MIRA) trial.Methods. Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosioes were used to assess disease severity and new erosions a t the last visit served as a proxy for progression.Results. At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-