A novel variant of the MHC-linked hsp70, hsp70-hom, is associated with rheumatoid arthritis

Tissue Antigens. 2000 Jul;56(1):38-44. doi: 10.1034/j.1399-0039.2000.560105.x.

Abstract

The three major histocompatibility complex (MHC)-linked hsp70s have been screened for variation in their 28 kDa C-terminal regions by direct nucleotide sequencing of the corresponding DNA fragments. No amino acid variation was detected in the major heat-inducible hsp70 (encoded by hsp70-1 and hsp70-2), although previously unreported silent mutations were identified in all three of the MHC-linked hsp70 genes. A novel coding polymorphism, a G to A transition, was identified at nucleotide 2763 of hsp70-hom (hom-2763). This dimorphism results in a glutamic acid to lysine alteration at position 602 in the C-terminal domain of hsp70-hom. The frequencies of the A-2763 and G-2763 alleles were calculated to be 27% and 73%, respectively. The hom-2763 dimorphism was characterised in 81 HLA-homozygous cell lines using an ARMS-PCR assay and A-2763 was found to be in strong linkage disequilibrium with DRB1*04 (Pc=1.31 x 10(-7), following Bonferoni's correction). Analysis of 60 rheumatoid arthritis (RA) families, each with an affected sib-pair, revealed an association between hsp70-hom A-2763 and RA using both the transmission disequilibrium test (TDT) and the transmission to sib-pair (Tsp) test (P=0.0038 and P=0.013, respectively). This association may be due to linkage disequilibrium with HLA-DR alleles, but could represent an additional risk factor for RA in the MHC class III region.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / genetics*
  • Genetic Linkage
  • HLA-DR Antigens / genetics
  • HLA-DRB1 Chains
  • HSP70 Heat-Shock Proteins / genetics*
  • Humans
  • Linkage Disequilibrium
  • Major Histocompatibility Complex / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide*

Substances

  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HSP70 Heat-Shock Proteins