Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA–DRB1*0405 and *0901

Abstract

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 × 10⁻²⁴, 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 84.3%, 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.