- Paper Report
- Open Access
Extended HLA haplotypes and RA susceptibility
- Derek Mattey1
© Biomed Central Ltd 2001
- Received: 26 March 2001
- Accepted: 26 July 2001
- Published: 26 July 2001
- rheumatoid arthritis
Many studies have shown that susceptibility to rheumatoid arthritis (RA) is associated with HLA-DRB1 alleles which encode similar amino acid sequences (QKRAA, QRRAA or RRRAA) in the third hypervariable region of the HLA-DR ? molecule. This provides the basis for the shared epitope (SE) hypothesis. An alternative RA protection (RAP) hypothesis has been proposed in which susceptibility to RA is conferred by HLA-DQ alleles (DQB1*03-DQA1*03 and DQB1*0501-DQA1*01) while protection is provided by DRB1 alleles encoding a DERAA motif instead of the SE. Other loci within the MHC may contribute to the linkage of this region with RA susceptibility, and some studies suggest that an extended MHC haplotype predisposes to RA. The aim of this study was to examine the possible contribution of genes other than DQ and DR to the association between HLA and RA.
The allele distribution of six microsatellites (D6S1014, D6S2673, D6STNFa, MIB, C1-2-5, and C1-3-2) located in the telomeric part of the HLA region was examined in RA patients and controls. Nineteen conserved microsatellite clusters (c1-c19) were identified within the controls. Twelve of these clusters were in linkage disequilibrium with DQB1-DRB1 haplotypes and corresponded to previously described ancestral haplotypes. The c1 haplotype contained an allele (MIB*350) which was associated with RA when analysed as part of a three point cluster at adjacent loci, i.e. within cluster D6S273*139-D6STNFa*99-MIB*350, D6STNFa*99-MIB*350-C1-2-5*196, or MIB*350-C1-2-5*196-C1-3-2*354. This association with RA at the MIB locus was independent of RA-predisposing DQB1-DRB1 haplotypes. The authors conclude that the telomeric part of the HLA region contains a genetic factor which predisposes to RA independently of the HLA class II genes; any locus between that encoding TNF-a and the end of the chromosome could be regarded as a candidate.
Case-control study, PCR, DNA sequencing
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