Identification of the NF-κB activating protein-like locus as a risk locus for rheumatoid arthritis
- Gang Xie1,3,
- Yue Lu2,
- Ye Sun1,3,
- Steven Shiyang Zhang1,
- Edward Clark Keystone3,
- Peter K Gregersen4,
- Robert M Plenge5,
- Christopher I Amos2,
- Katherine A Siminovitch1,3,6
- 1Mount Sinai Hospital Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
- 2Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
- 3Rebecca MacDonald Centre for Arthritis, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
- 4Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA
- 5Division of Rheumatology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
- 6Departments of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Correspondence to Dr Katherine A Siminovitch, Mount Sinai Hospital, Lunenfeld Research Institute and Toronto General Research Institute, 600 University Ave, Room 778D, Toronto, Ontario, Canada M5G 1X5;
- Received 23 May 2012
- Accepted 21 October 2012
- Published Online First 6 December 2012
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.
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