title: Identification of the NF-κB activating protein-like locus as a risk locus for rheumatoid arthritis.
abstract: OBJECTIVE
  To fine-map the NF-κB activating protein-like (NKAPL) locus identified in a prior genome-wide study as a possible rheumatoid arthritis (RA) risk locus and thereby delineate additional variants with stronger and/or independent disease association.
  
  
  METHODS
  Genotypes for 101 SNPs across the NKAPL locus on chromosome 6p22.1 were obtained on 1368 Canadian RA cases and 1471 controls. Single marker associations were examined using logistic regression and the most strongly associated NKAPL locus SNPs then typed in another Canadian and a US-based RA case/control cohort.
  
  
  RESULTS
  Fine-mapping analyses identified six NKAPL locus variants in a single haplotype block showing association with p≤5.6×10(-8) in the combined Canadian cohort. Among these SNPs, rs35656932 in the zinc finger 193 gene and rs13208096 in the NKAPL gene remained significant after conditional logistic regression, contributed independently to risk for disease, and were replicated in the US cohort (Pcomb=4.24×10(-10) and 2.44×10(-9), respectively). These associations remained significant after conditioning on SNPs tagging the HLA-shared epitope (SE) DRB1*0401 allele and were significantly stronger in the HLA-SE negative versus positive subgroup, with a significant negative interaction apparent between HLA-DRB1 SE and NKAPL risk alleles.
  
  
  CONCLUSIONS
  By illuminating additional NKAPL variants with highly significant effects on risk that are distinct from, but interactive with those arising from the HLA-DRB1 locus, our data conclusively identify NKAPL as an RA susceptibility locus.
authors.affiliation: Mount Sinai Hospital Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.forename: Steven Shiyang
authors.initials: SS
authors.lastname: Zhang
authors.forename: Edward Clark
authors.initials: EC
authors.lastname: Keystone
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002170:Canada; D016022:Case-Control Studies; D056970:Co-Repressor Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014481:United States
chemical_list: D056970:Co-Repressor Proteins; C569368:NKAPL protein, human; D009687:Nuclear Proteins