Interaction between RANKL and HLA–DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort

Abstract

Objective. To determine whether the RANKL and HLA-DRB1 "shared epitope" (SE) genotypes contribute to the development of rheumatoid arthritis (RA).Methods. We studied 237 patients with early RA (within 15 months of symptom onset) who were seropositive for rheumatoid factor. HLA-DRB1 genotyping was performed using the polymerase chain reaction (PCR)-based oligonucleotide probe assay. RANKL polymorphisms were analyzed using PCR pyrosequencing for SNP1 and fluorescence-based PCR for the presence or absence of the TAAA insertion.Results. The presence of SE-containing DRB1*04 alleles was associated with an earlier age at RA onset (mean ؎ SD 47 ؎ 12.7 years versus 53 ؎ 12.5 years in SE-patients; P ‫؍‬ 0.0004). The 2 novel RANKL polymorphisms were in strong linkage disequilibrium (P < 0.0001) and were associated with earlier ages at disease onset (e.g., for the CC versus CT/TT genotypes, 44 ؎ 13.5 years versus 51 ؎ 12.7 years; P ‫؍‬ 0.0080). The mean age at disease onset in SE؉ patients with the RANKL-CC genotype (35 ؎ 7.2 years) was a mean of 18 years younger than in SE-patients with RANKL-CT/TT (53 ؎ 12.5 years; P < 0.0001) and was 17 years younger than in SE-patients with RANKL-CC (52 ؎ 13.2 years; P ‫؍‬ 0.0005). The proportion of patients with both the SE and RANKL risk alleles was highest ( Conclusion. This study provides the first evidence that novel RANKL polymorphisms were associated with

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

“…Although the SE was associated with an earlier onset of RA in our patients (42), our results suggest that SE had no significant influence on the disease activity, disability, baseline radiographic damage scores, or responses to followup treatments in our cohort of patients with early RFϩ disease. In our cohort, the possible associations between SE and radiographic progression rates are perplexing and appear to vary depending on the analysis methods.…”

“…In this study, we examined whether the presence of the SE and/or the TNFA -308 G-to-A polymorphism independently or in combination was associated with radiographic damage in an observational cohort of patients with early (median of 5.6 months since symptom onset), active, seropositive RA (39)(40)(41)(42).…”

Understanding the genetic contribution to rheumatoid arthritis

“…For a large number of genes suggested to be relevant in the pathophysiology of RA, association was observed in only one study without replication such as b-adrenergic receptor gene SNPs, RANKL, ICAM-1, VEGF, PDCD-1, and IL1-RA gene or data were published describing a lack of association with RA such as CTLA-4, CCR5, mannose-binding-lectin, Toll-like receptor 2 or 4 gene variants [41][42][43][44][45][46][47][48][49][50].…”

Single-factor scoring validation for the Health Assessment Questionnaire-Disability Index (HAQ-DI) in patients with systemic sclerosis and comparison with early rheumatoid arthritis patients

“…The consortium has been described in detail in previous publications [15,16]. Briefly, patients in this subset had a diagnosis of early RA (median duration was 5.2 months since symptom onset, disease duration was less than 15 months), had no previous disease modifying antirheumatic drug treatment, were rheumatoid factor seropositive (RF median 214 IU/ml), and had ‡6 swollen joints and ‡9 tender joints.…”