Abstract
Ankylosing spondylitis (AS) is polygenic with contributions from the immunologically relevant genes HLA-B*27, ERAP1 and IL23R. A recent genome-wide association screen (GWAS) identified associations (P∼0.005) with the non-synonymous single-nucleotide polymorphisms (nsSNPs), rs4077515 and rs3812571, in caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) on chromosome 9q that had previously been linked to AS. We replicated these associations in a study of 730 AS patients compared with 2879 historic disease controls (rs4077515 P=0.0004, odds ratio (OR)=1.2, 95% confidence interval (CI)=1.1–1.4; rs3812571 P=0.0003, OR=1.2, 95% CI=1.1–1.4). Meta-analysis revealed strong associations of both SNPs with AS, rs4077515 P=0.000005, OR=1.2, 95% CI=1.1–1.3 and rs3812571 P=0.000006, OR=1.2, 95% CI=1.1–1.3. We then typed 1604 AS cases and 1020 controls for 13 tagging SNPs; 6 showed at least nominal association, 5 of which were in CARD9. We imputed genotypes for 13 additional SNPs but none was more strongly associated with AS than the tagging SNPs. Finally, interrogation of an mRNA expression database revealed that the SNPs most strongly associated with AS (or in strong linkage disequilibrium) were those most associated with CARD9 expression. CARD9 is a plausible candidate for AS given its central role in the innate immune response.
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Acknowledgements
JP is funded by the NIHR Oxford Biomedical Research Centre ankylosing spondylitis chronic disease cohort (Theme Code: A91202). DH is funded by the National Ankylosing Spondylitis Society (UK). CF is funded by The Thames Valley Comprehensive Local Research Network (TVCLRN), which forms part of the NIHR Comprehensive Clinical Research Network (CCRN). TK is funded by the Henni Mester studentship. This study was funded, in part, by the Arthritis Research UK, award numbers 18797 and 19356 and by the Wellcome Trust under award no. 076113. We are grateful to the many patients who contributed samples to these studies and to their physicians for allowing us to study their patients. We also thank the National Ankylosing Spondylitis Society (UK) for additional financial support and their unstinting help in patient recruitment. We thank the Osteoarthritis Group, Oxford for the use of their control samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the data is available at http://www.wtccc.org.uk. We acknowledge the use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Additional laboratory support was provided by the NIHR Oxford Musculoskeletal Biomedical Research Unit. Finally, we thank Lyn-Louise Johnson for iPLEX genotyping and the Bioinformatics and Statistical Genetics groups for support, both of the Wellcome Trust Centre for Human Genetics, Oxford.
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Pointon, J., Harvey, D., Karaderi, T. et al. Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene. Genes Immun 11, 490–496 (2010). https://doi.org/10.1038/gene.2010.17
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DOI: https://doi.org/10.1038/gene.2010.17
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