HLA-DRB1, especially the shared
epitope (SE), is strongly associated with
rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated
peptide/
protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific
HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for
rheumatoid factor (RF).
HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used.
HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result,
HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (pā=ā8.8×10(-6) and 0.0011, OR: 1.57 (1.28-1.91) and 1.37 (1.13-1.65), respectively). We also found that
HLA-DR14 and the
HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (pā=ā0.00022 and 0.00013, OR: 1.52 (1.21-1.89) and 3.08 (1.68-5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with
HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with
HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the
HLA-DR8 homozygote.