Increased susceptibility to rheumatoid arthritis in koreans heterozygous for HLA-DRB1*0405 and *0901

Objective. To investigate the association of susceptibility and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in an Asian population. Methods. All RA patients (n = 574) and control subjects (n = 392) were Korean. HLA-DRB1 typing and further subtyping of all alleles was performed by polymerase chain reaction, sequence-specific oligonucleotide probe hybridization, and direct DNA sequencing analysis. We used a relative predispositional effects (RPEs) method and a false discovery rate correction method for multiple comparisons. Results. The DRB1*0405 and *0901 alleles showed the most significant associations with RA (P = 7.83 × 10²⁴, odds ratio [OR] 4.40 [95% confidence interval (95% CI) 3.24-5.99], and P = 3.76 × 10^-9, OR 2.47 [95% CI 1.82-3.36], respectively). The RPEs test showed that the DRB1*0401 and *0410 alleles conferred susceptibility and that the DRB1*0701, *0802, *1301, *1302, *1403, and *1405 alleles showed significant protective effects. Susceptibility and protective alleles both showed a pattern consistent with additive genetic effects, and each influenced RA independently of the other. The compound heterozygote DRB1*0405/ *0901 was associated with the highest risk of RA (corrected P = 1.81 × 10^-11, OR 58.2 [95% CI 7.95-425.70]). The mean age at disease onset was ∼4 years earlier or was 3 years earlier, respectively, in patients with at least 1 copy of the DRB1*0405 or the DRB1*0901 allele. Radiographic changes (stages II-IV) were more frequent in patients with at least 1 copy of DRB1*0405 (P = 0.032, 92.6% versus §4.3%, OR 2.33 [95% CI 1.24-4.39]). Conclusion. The DRB1*0405/*0901 heterozygote has the strongest association with RA, suggesting that this heterozygote enhances the susceptibility to RA in Koreans.