title: Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene.
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 approximately 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.
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit and Botnar Research Centre, Oxford, UK. jennyp@well.ox.ac.uk
authors.forename: J J
authors.initials: JJ
authors.lastname: Pointon
authors.forename: D
authors.initials: D
authors.lastname: Harvey
authors.forename: T
authors.initials: T
authors.lastname: Karaderi
authors.forename: L H
authors.initials: LH
authors.lastname: Appleton
authors.forename: C
authors.initials: C
authors.lastname: Farrar
authors.forename: M A
authors.initials: MA
authors.lastname: Stone
authors.forename: R D
authors.initials: RD
authors.lastname: Sturrock
authors.forename: M A
authors.initials: MA
authors.lastname: Brown
authors.forename: B P
authors.initials: BP
authors.lastname: Wordsworth
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013167:Spondylitis, Ankylosing / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D004268:DNA-Binding Proteins; C116351:SNAPC4 protein, human; D014157:Transcription Factors
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