High resolution mapping in the major histocompatibility complex region identifies multiple independent novel loci for psoriatic arthritis
- Proton Rahman1,
- Nicole M Roslin2,
- Fawnda J Pellett3,
- Mathieu Lemire4,
- Celia M T Greenwood5,6,
- Joseph Beyene2,7,
- Angela Pope8,
- Lynette Peddle8,
- Andrew D Paterson6,9,
- Mohammed Uddin10,
- Dafna D Gladman11
- 1Division of Rheumatology, Memorial University, St John's, Newfoundland, Canada
- 2Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
- 3Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada
- 4Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- 5Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
- 6Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- 7Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
- 8Newfound Genomics, St John's, Newfoundland, Canada
- 9Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
- 10Memorial University, St John's, Newfoundland, Canada
- 11Division of Rheumatology, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada
- Correspondence to Dr Dafna D Gladman, Centre for Prognosis Studies in The Rheumatic Diseases, Toronto Western Research Institute, Toronto Western Hospital, 399 Bathurst Street, 1E-410B, Toronto, Ontario M5T 2S8, Canada;
- Accepted 7 November 2010
- Published Online First 17 January 2011
Objective Psoriatic arthritis (PsA) has a clear familial predisposition, the major histocompatibility complex (MHC) region being the strongest genetic locus. The study primary objective was to identify single nucleotide polymorphisms (SNPs) independent of known human leucocyte antigen (HLA) alleles within the MHC region that are associated with PsA using a high-density SNP map.
Method In all, 914 samples were assessed, including 427 PsA cases from 2 well established PsA cohorts and 487 controls from Canada. The genotype data consisted of 2521 SNPs from 2 Illumina Goldengate MHC panels, spanning 4.9 Mb of chromosome 6 with an average spacing of 2 kb. Classical HLA alleles were genotyped in all subjects using sequence-specific oligonucleotide probes or sequence-specific primers. A conditioning approach was used to distinguish between new associations and those in linkage disequilibrium (LD) with known HLA alleles.
Results Unconditional association analysis revealed 43 markers with p<7.26×10−5 (calculated experiment-wide significance threshold). In the conditional analysis, 10 SNPs showed statistically significant association at a threshold of p<7.26×10−5. Seven SNPs were in strong LD in the study data (pairwise r2 >0.77 in the controls) reflecting one association signal. These SNPs spanned a 1.6 Mb region. SNP rs1150735 is 1.5 kb upstream from ring finger protein 39 (RNF39). RNF39 SNPs have been associated with HIV1 disease progression and set point CD4 T cell count.
Conclusion Four new loci for either psoriasis or PsA in the MHC region that are independent of known HLA alleles have been identified. The effect size of these variants is modest. Replication of these variants in multiple larger populations is necessary.
PR and NMR contributed equally to this work.
Competing interests None.
Ethics approval This study was conducted with the approval of the University of Toronto, Toronto Ontario and Memorial University, St John's, Newfoundland, Canada.
Provenance and peer review Not commissioned; externally peer reviewed.