Elucidating the Chromosome 9 Association with AS; CARD9 is a Candidate Gene

Ankylosing spondylitis (AS) is polygenic with contributions from the immunologically relevant genes HLA-B*27, ERAP1 and IL23R. A recent genome-wide association study (GWAS) identified associations (p~0.005) with the non-synonymous single nucleotide polymorphisms (nsSNPs), rs4077515 and rs3812571, in CARD9 and SNAPC4 on chromosome 9q that had previously been linked to AS. We replicated these associations in a study of 730 AS patients compared to 2879 historic disease controls, (rs4077515 p = 0.0004 odds ratio (OR) (95% confidence interval) = 1.2 (1.1-1.4); rs3812571 p = 0.0003 OR = 1.2 (1.1-1.4)). Meta-analysis revealed strong associations of both SNPs with AS, rs4077515 p = 0.000005 OR = 1.2 (1.1-1.3) and rs3812571 p = 0.000006 OR = 1.2 (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 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.