A variant of HLA–DR4 determines susceptibility to rheumatoid arthritis in a subset of Israeli Jews

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Abstract
HLA–DR4 is associated with risk for developing rheumatoid arthritis (RA) in most populations. In Israeli Jews, in whom the Dw10 subtype of DR4 predominates, no association of RA with DR4 has been found. The inability to detect an association could be due to the high frequency of DR4‐Dw10. We used DNA typing with amplification by the polymerase chain reaction and dot‐blotting with allele‐specific oligonucleotides to determine DR4 variants in 131 Jewish RA patients living in Israel and 134 controls. In both Ashkenazi Jews and non‐Ashkenazi Jews, the rare variant Dw15 (previously identified in Japanese populations and in Japanese patients with RA) was found to be the main allele associated with the risk of developing RA (relative risk = 9.2, corrected P < 0.001). However, this low‐frequency allele could be responsible for susceptibility in only 11.5% of the patients. Susceptibility for rheumatoid factor–positive RA was associated with Dw4 and Dw15; the risk for rheumatoid factor–negative RA was associated only with Dw14. The distribution of the HLA–DQ alleles associated with DR4 showed that more than half of the RA patients with Dw15 also had HLA–DQw2. The frequencies of DQw7 and DQw8 were not different in RA patients compared with controls. The results suggest that, as in other populations, susceptibility for the development of RA in Israeli Jews is associated with DRB1 locus alleles of the DR4 group.