MAST3: a novel IBD risk factor that modulates TLR4 signaling.
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 genome-wide 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 1, 1530 single-nucleotide polymorphisms (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 2). One intronic variant, rs273506, located in the microtubule-associated serine/threonine-protein kinase gene-3 (MAST3), was found to be associated in both stages (pooled P=1.8 x 10(-4)). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated with 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 Toll-like receptor-4-dependent NF-kappaB activity. Our findings are additional proofs of the pivotal role played by modulators of NF-kappaB activity in IBD pathogenesis.
Labbé
C
C
Institut de Cardiologie de Montréal, Montréal, Québec, Canada.
Goyette
P
P
Lefebvre
C
C
Stevens
C
C
Green
T
T
Tello-Ruiz
M K
MK
Cao
Z
Z
Landry
A L
AL
Stempak
J
J
Annese
V
V
Latiano
A
A
Brant
S R
SR
Duerr
R H
RH
Taylor
K D
KD
Cho
J H
JH
Steinhart
A H
AH
Daly
M J
MJ
Silverberg
M S
MS
Xavier
R J
RJ
Rioux
J D
JD
D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism / Q000502:physiology*
D018941:Antigens, CD19; D008869:Microtubule-Associated Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C544700:MAST3 protein, human; D017346:Protein Serine-Threonine Kinases