title: Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci.
abstract: OBJECTIVE
  Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone.
  
  
  METHODS
  We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci.
  
  
  RESULTS
  Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93).
  
  
  CONCLUSIONS
  This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.
authors.affiliation: ARC Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK.
authors.forename: Annie
authors.initials: A
authors.lastname: McClure
authors.forename: Mark
authors.initials: M
authors.lastname: Lunt
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Xiayi
authors.initials: X
authors.lastname: Ke
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.forename: Laura
authors.initials: L
authors.lastname: Gibbons
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Ioanna
authors.initials: I
authors.lastname: Marinou
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Sophia
authors.initials: S
authors.lastname: Steer
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: Pille
authors.initials: P
authors.lastname: Harrison
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D003362:Cost-Benefit Analysis; D005240:Feasibility Studies; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000191:economics / Q000379:methods*; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010456:Peptides, Cyclic / Q000276:immunology; D012680:Sensitivity and Specificity; D012737:Sex Factors; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide