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Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus.
Kilding R, Iles M, Timms J, Worthington J, Wilson A
Arthritis Rheum. 2004;50( 3):763-9.
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Abstract
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). CONCLUSION: 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.
Keyword(s)
Alleles; Chromosome Mapping; Epitopes; Human; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Support, Non-U.S. Gov't; genetics: Arthritis, Rheumatoid; genetics: Genetic Predisposition to Disease; genetics: HLA-DR Antigens; genetics: Telomere