Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus.
OBJECTIVE
Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location.


METHODS
We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs).


RESULTS
Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 x 10(-5)) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P = 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and PG8 (P = 0.003).


CONCLUSIONS
At least 1 additional non-DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes.
Kilding
Rachael
R
The University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.
Iles
Mark M
MM
Timms
Janine M
JM
Worthington
Jane
J
Wilson
Anthony G
AG
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D002874:Chromosome Mapping; D000939:Epitopes; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D016615:Telomere / Q000235:genetics*
D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains