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

Arthritis Rheum. 2004 Oct;50(10):3093-103. doi: 10.1002/art.20555.


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 (23%) in those who developed RA during their third decade of life (ages 20-30 years), with a declining trend among those who developed RA during their fourth (16%), fifth (5%), and sixth or later (0%) decades. Interestingly, 92% of the patients diagnosed as having RA between ages 20 and 30 years carried at least 1 of the RA-associated DRB1*04 alleles, suggesting a strong influence of the SE in the early onset of RA. The majority of patients who developed RA symptoms in their third to fifth decades (74 of 119 [62%]) carried at least 1 copy of the DRB1*04 alleles; in contrast, fewer than half of the patients who developed RA in their sixth decade or later (50 of 118 [42%]) had DRB1*04 alleles. RANKL genotypes were not associated with erosive disease at baseline or with the yearly progression rate of radiographic joint damage.

Conclusion: This study provides the first evidence that novel RANKL polymorphisms were associated with an earlier age at RA onset in SE+, but not SE-, patients and that an interaction between SE-containing HLA-DRB1 and RANKL polymorphisms increased the disease penetrance, resulting in a mean age at RA onset that was 18-20 years younger. Our results also suggested genetic differences between patients with early-onset and those with late-onset RA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Arthritis, Rheumatoid / epidemiology*
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology
  • Carrier Proteins / genetics*
  • Female
  • Genotype
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Penetrance
  • Polymorphism, Genetic
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Rheumatoid Factor / blood


  • Carrier Proteins
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Membrane Glycoproteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Rheumatoid Factor