HLA‐DR1 and rheumatoid arthntis in Israeli Jews: Sequencing reveals that DRB1*0102 is the predominant HLA‐DR1 subtype

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Abstract
Rheumatoid arthritis (RA) is associated with the HLA‐DR4 cellular subtypes Dw4 and Dw14 in Caucasians, with Dw15 in Japanese, and possibly with HLA‐DR1 in Israeli Jews. Sequencing studies in Caucasians have shown that these molecules share a common amino acid sequence in the third hypervariable region of the DR molecule (AA 67‐74: LLEQRRAA or LLEQKRAA), suggesting that this sequence is primarily associated with RA. An important argument in favor of this shared‐epitope hypothesis has been the reported association between DR1 and RA in Israeli Jews. However, a later report did not confirm this association, and cellular typing showed that Israeli DR1 consists of three or more subtypes, suggesting that new subtypes might be present. Since no sequencing data on Israeli HLA‐DR1 genes have been reported, we sequenced the first domain (AA 10–91) of the DRB1 gene in 12 DR1‐positive Israeli RA patients, 5 healthy controls and a homozygous typing cell (HTC), defining the major Jewish cellular HLA‐DR1 subtype. DRB1*0102 (DR1 Dw20) was found in 8 RA patients, 3 controls and the HTC “LVA”. DRB1*0101 (DR1 Dw1) was found in 4 RA patients and 2 controls. No other DR1 subtypes were encountered. In all 20 DR1 haplotypes, the DRB1*0101 or 0102 allele was associated with DQA1*0101 and DQB1*0501, being identical to the Caucasian DR1 haplotypes. Thus, at the sequence level, we found no basis for the reported extensive cellular heterogeneity of DR1 in the Israeli population. Both alleles encountered, DRB1*0102 or DRB1*0101, encode a third hypervariable region sequence (AA 67–74) shared with DRB1*0404, 0405, 0408 and 0410.