Identification of a two-loci epistatic interaction associated with susceptibility to rheumatoid arthritis through reverse engineering and multifactor dimensionality reduction.
Altered synovial fibroblast (SF) transcriptional activity is a key factor in the disease progression of rheumatoid arthritis (RA). To determine the transcriptional regulatory network associated with SF response to an RA proinflammatory stimulus we applied a CARRIE reverse engineering approach to microarray gene expression data from SFs treated with RA synovial fluid. The association of the inferred gene network with RA susceptibility was further analyzed by a case-control study of promoter single-nucleotide polymorphisms, and the presence of epistatic interactions was determined using the multifactor dimensionality reduction methodology. Our findings suggest that a specific NF-kappaB transcriptional regulatory network of 13 genes is associated with SF response to RA proinflammatory stimulus and identify a significant epistatic association of two of its genes, IL6 and IL4I1, with RA susceptibility.
Julià
Antonio
A
Unitat de Recerca de Reumatologia, Institut de Recerca Hospital Universitari Vall d'Hebron, UAB, 08035 Barcelona, Spain.
Moore
Jason
J
Miquel
Laia
L
Alegre
Cayetano
C
Barceló
Pere
P
Ritchie
Marylyn
M
Marsal
Sara
S
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004843:Epistasis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005818:Genetic Engineering; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D013582:Synovial Fluid / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism
D005819:Genetic Markers; D016328:NF-kappa B