A novel variant of the MHC-linked hsp70, hsp70-hom, is associated with rheumatoid arthritis.
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.
Jenkins
S C
SC
Department of Biochemistry, University of Oxford, United Kingdom.
March
R E
RE
Campbell
R D
RD
Milner
C M
CM
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D008040:Genetic Linkage; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins