title: Evidence for a novel rheumatoid arthritis susceptibility locus on chromosome 6p.
abstract: OBJECTIVE
  To investigate whether the large linkage peak on chromosome 6p harbors rheumatoid arthritis (RA) susceptibility loci in addition to the well-characterized HLA-DRB1 gene.
  
  
  METHODS
  DNA samples obtained from 377 UK RA affected sibling pair (ASP) families, comprising test (181 ASPs) and replication (196 ASPs) cohorts, were used for linkage analysis. Three hundred eighty-four patients with RA derived from a subset of 192 ASPs were compared with a panel of 288 unrelated healthy controls for association studies. Samples were genotyped for 35 microsatellites and 25 single-nucleotide polymorphisms (SNPs).
  
  
  RESULTS
  In the test cohort, the maximum logarithm of odds (LOD) score was obtained over D6S1260 (LOD 7.1). Evidence for linkage to the telomeric portion of the peak was increased in subsets of ASPs in which both individuals had erosive disease or both carried 2 copies of the shared epitope. HLA-A, HLA-DRB1, and 8 additional markers showed evidence of linkage in the presence of association with RA (using the extended transmission disequilibrium test [ETDT]). The positive ETDT result for 2 adjacent markers (D6S1665 and 210901-4) mapping to the telomeric end of the linked region ( approximately 11 Mb from DRB1) was replicated (for D6S1665) in the second cohort of ASPs. Haplotypic overtransmission of pairwise combinations between D6S1665*7 and 210901-4*4 was identified through the TDTPhase program. Multipoint conditional analysis showed this effect to be independent of HLA-DRB1. SNP-based association studies of the region identified a 4-marker haplotype in the DEK gene that was significantly associated with RA (P = 0.009).
  
  
  CONCLUSIONS
  Evidence has been presented for an RA susceptibility locus mapping under the linkage peak on 6p, 11 Mb telomeric of HLA-DRB1. Preliminary association data implicate the gene DEK.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: William
authors.initials: W
authors.lastname: Brintnell
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Stephen
authors.initials: S
authors.lastname: Eyre
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Silman
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
mesh_terms: D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D035781:Siblings; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains