Abstract
Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genomewide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage one, 1530 SNPs were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage two). One intronic variant, rs273506 located in the
MAST3
gene was found to be associated in both stages (pooled P=2×10
−4
). We identified four
MAST3
coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated to IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays which showed abundant expression of
MAST3
in antigen presenting cells and in lymphocytes. The knockdown of
MAST3
specifically decreased TLR4 dependent NF-κB activity. Our findings are additional proof of the pivotal role played by modulators of NF-κB activity in IBD pathogenesis.