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Investigation of association of genes NAT9, SLC9A3R1 and RAPTOR on chromosome 17q25 with psoriatic arthritis
  1. C E Filer,
  2. P Ho,
  3. I N Bruce,
  4. J Worthington,
  5. A Barton
  1. ARC-Epidemiology Unit, University of Manchester, Manchester, UK
  1. C E Filer, ARC-EU, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; charliefiler{at}doctors.org.uk

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Psoriatic arthritis (PsA) is defined as “an inflammatory arthritis associated with psoriasis that is usually negative for rheumatoid factor”.1 A strong genetic component to disease aetiology is suggested by the sibling recurrence risk (λs), which has been estimated to be between 27–55 and is higher than that for psoriasis alone (λs ∼4), suggesting an even stronger genetic component to disease.13 Previous work has implicated the human leukocyte antigen (HLA) region in conferring susceptibility to PsA. For example, several reports have found higher frequencies of the HLA B locus alleles, including HLA B27, in PsA participants compared to controls or patients with psoriasis.4 However, a recent study in a UK population did not show any contribution of HLA DRB1 or HLA Cw6, the major susceptibility variants for rheumatoid arthritis and psoriasis, respectively to PsA itself.5

Analysis in psoriasis families has identified a locus at chromosome 17q25 that shows evidence for linkage, which is stronger in those families with joint complaints.6 Association studies of this locus and, in particular, of the gene RAPTOR and the Runt-related transcription factor (RUNX)1 binding site between genes NAT9 and SLC9A3R1 have revealed conflicting evidence for association with psoriasis.79 For example, a single nucleotide polymorphism (SNP) mapping between the NAT9 and SCL9A3R1 genes and altering a RUNX1 binding site was associated with psoriasis in one study7 but this has not been replicated subsequently.8 9

We hypothesised that these loci may actually be important susceptibility factors for PsA rather than psoriasis. We aimed to investigate the association of SNPs spanning the NAT9, SCL9A3R1 and RAPTOR loci with susceptibility to PsA.

A total of 25 SNPs were selected for genotyping from available HapMap phase1 data (http://www.hapmap.org): 6 mapping to the NAT9 locus; 13 mapping to the SLC9A3R1 gene region, 3 SNPs between the NAT9 and SLC9A3R1 genes (including the SNP affecting the RUNX1 binding site) and 3 mapping to intron 3 of the RAPTOR gene, as these had previously been reported to be associated with psoriasis susceptibility.6 Allele and genotype frequencies for all 25 SNPs were compared between PsA samples (n = 353) and population controls (n = 351). The case and control cohorts have been described previously10 but, briefly, all patients were white Caucasians and all were British. Of the patients with PsA, 58% were female and 42% were male. The mean (range) disease duration of their arthritis was 10 (5–19) years and 22% were rheumatoid factor positive. The patients with PsA all satisfied the Classification of Psoriatic Arthritis (CASPAR) criteria for PsA.9 Genotyping was performed using the Sequenom MassArray platform (http://www.sequenom.com). This study was approved by the North West Multicentre Research Ethics Committee and all participants provided informed consent.

Genotype frequencies for PsA cases and controls conformed to Hardy–Weinberg expectations and allele frequencies were similar to those previously reported in European populations.

Two SNPs within the gene NAT9 showed evidence for association with PsA rs2305213 (p = 0.027) and rs4788850 (p = 0.028). The SNPs were highly correlated (r2 = 0.95) and so haplotype analysis was not undertaken. These SNPs are different to those previously reported to be associated with psoriasis. No association between PsA and the genotyped SNPs tested within the SLC9A3R1gene (including the SNP affecting the RUNX1 binding site) and the RAPTOR gene was identified.

In order to validate this putative association, 165 additional PsA cases and 1908 controls were genotyped for the 2 NAT9 SNPs. In the combined cohort of 518 PsA cases and 2259 controls, genotype frequencies for both SNPs conformed to Hardy–Weinberg expectations but neither remained significantly associated with PsA (table 1).

Table 1 Genotype frequencies of rs230513 and rs488850 in gene NAT9 for psoriatic arthritis (PsA) cases and controls

We have found no evidence for association of SNPs mapping to the NAT9, SLC9A3R1 and RAPTOR loci with susceptibility to PsA. The study illustrates the importance of large sample sizes to avoid spurious associations.

REFERENCES

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Footnotes

  • Competing interests: None declared.

  • Ethics approval: This study was approved by the North West Multicentre Research Ethics Committee and all participants provided informed consent.