Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene

Area of Science:

• Genetics
• Immunology
• Rheumatology

Background:

• Ankylosing spondylitis (AS) is a polygenic inflammatory disease.
• Key genes like HLA-B*27, ERAP1, and IL23R are known contributors.
• Previous genome-wide association screens (GWAS) suggested links to chromosome 9q, specifically to CARD9 and SNAPC4.

Purpose of the Study:

• To replicate and validate associations of non-synonymous single-nucleotide polymorphisms (nsSNPs) rs4077515 and rs3812571 in CARD9 and SNAPC4 with Ankylosing spondylitis (AS).
• To further investigate the genetic association of CARD9 with AS through additional tagging and imputed SNPs.
• To explore the relationship between associated SNPs, CARD9 gene expression, and AS susceptibility.

Main Methods:

• Replication study using 730 AS patients and 2879 disease controls.
• Meta-analysis combining study data with previous GWAS findings.
• Genotyping of 13 tagging SNPs and imputation of 13 additional SNPs in a larger cohort (1604 AS cases, 1020 controls).
• Analysis of mRNA expression data to correlate SNP association with CARD9 expression levels.

Main Results:

• Replication confirmed significant associations for rs4077515 (P=0.0004, OR=1.2) and rs3812571 (P=0.0003, OR=1.2) with AS.
• Meta-analysis showed strong associations for both SNPs (rs4077515 P=5x10^-6, OR=1.2; rs3812571 P=6x10^-6, OR=1.2).
• Five out of six associated SNPs were located within the CARD9 gene.
• SNPs strongly associated with AS were also associated with higher CARD9 mRNA expression.

Conclusions:

• The study provides robust genetic evidence supporting the association between CARD9 and Ankylosing spondylitis.
• CARD9 is implicated as a significant genetic risk factor for AS, likely due to its role in innate immunity.
• These findings highlight CARD9 as a potential therapeutic target for AS.