Rheumatology Advance Access originally published online on July 19, 2005
Rheumatology 2005 44(9):1196; doi:10.1093/rheumatology/kei009
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LETTER TO THE EDITOR |
RUNX1 intronic SNP is not associated with rheumatoid arthritis susceptibility in Dutch Caucasians
Department of Rheumatology and 1 Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
Correspondence to: J. Wesoly, Department of Rheumatology, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands. E-mail: j.z.wesoly{at}lumc.nl
SIR, Among a number of genes, RUNX1, a haematopoietic transcription activator and repressor, has been recently identified as a rheumatoid arthritis (RA) susceptibility gene [1]. In order to replicate and confirm this finding, we set out to determine the genotype and allele frequencies of RUNX1 intronic gene variant (rs2268277) in a Caucasian population of RA patients.
Six hundred and sixty-five RA patients and 632 ethnically matched controls were included in the analysis. All RA patients fulfilled criteria of the American College of Rheumatology. Our institutional review board (Commissie Medische Ethiek) approved all protocols and subjects were enrolled with informed consent. Three hundred and ninety of the patients were participants in the population-based arthritis inception cohort [2]; shared epitope (SE) genotyping (n = 313) and serological [rheumatoid factor (RF), n = 254; antibodies to cyclic citrullinated peptide (anti-CCP), n = 341] data were available for the patients. The other 275 patients were consecutive patients from an out-patient clinic and have been described by Brinkman et al. [3].
Patients and controls were genotyped for the RUNX1 SNP using time-of-flight mass spectrometry based Sequenom Mass Array Platform (Sequenom, San Diego, CA, USA). In both groups genotypes were in Hardy–Weinberg equilibrium. The 
2 test was used for association analysis.
Interestingly, in contrast with a previous report [1], we did not observe a significant difference in genotype frequencies between patients and controls, as shown in Table 1. Similarly, the minor allele frequencies did not vary between the two groups (0.36 vs 0.35, P = 0.46).
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To study whether any opposing associations were seen in subgroups that led to a lack of overall effect, we extended the analysis to stratification of the RA cohort on SE status. In this analysis, no differences in minor allele frequencies between the groups were identified (0.33 vs 0.29, P = 0.28). We also studied the frequency of the risk allele in RA patients stratified by the presence of anti-CCP and the presence of IgM RF. In comparison with the controls, no association of the risk allele was detected, either for the anti-CCP positive (0.32 vs 0.33, P = 0.65) or the negative patient group (0.35 vs 0.33, P = 0.69). Similarly, no differences in allele frequency were observed after stratification of the RA group into RF-positive and RF-negative patients, in comparison with controls (0.36 and 0.3 vs 0.33, P = 0.26 and P = 0.43, respectively).
It is unlikely that this intronic SNP or another RUNX1 polymorphism in linkage disequilibrium (LD) with the SNP analysed here is a functional variant in our population. The inconsistencies could be explained by a possible difference in LD between the Japanese and European populations; if this were the case, the intronic RUNX1 SNP might not be a good marker to use to explain previously observed effects [1].
Association of the polymorphism in intron 6 of RUNX1 has also been investigated in the Newfoundland cohort of patients with psoriatic arthritis (PsA), which was defined as an autoimmune disease combining features of RA, psoriasis and inflammatory bowel disease [4]. Similarly to our findings, no association of RUNX1 SNP with PsA was observed in this analysis. The current data suggest that RUNX1 is not an RA susceptibility gene for the Western European population but may still be of relevance in Asian populations.
This study was supported by the Center for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomic Initiative/Netherlands Organization for Scientific Research (NWO).
The authors have declared no conflicts of interest.
References
- Tokuhiro S, Yamada R, Chang X et al. An intronic SNP in RUNX1 binding site of SLC22A4 encoding an organic cation transporter is associated with rheumatoid arthritis. Nat Genet 2003;35:341–8.[CrossRef][Web of Science][Medline]
- van Aken J, van Bilsen JH, Allart CF, Huizinga TW, Breedveld FC. The Leiden Early Arthritis Clinic. Clin Exp Rheumatol 2003;21(5 Suppl. 31):S100–5.
- Brinkman BM, Huizinga TW, Kurban SS, van der Velde EA. Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? Br J Rheumatol 1997;36:516–21.
[Abstract/Free Full Text] - Butt C, Sun S, Greenwood C, Gladman D, Rahman P. Lack of association of SLC22A4, SLC22A5, SLC9A3R1 and RUNX1 variants in psoriatic arthritis. Rheumatology 2005;44:820–1.
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