Rheumatoid arthritis-associated gene-gene interaction network for rheumatoid arthritis candidate genes

Abstract

Rheumatoid arthritis (RA, MIM 180300) is a chronic and complex autoimmune disease. Using the North American Rheumatoid Arthritis Consortium (NARAC) data set provided in Genetic Analysis Workshop 16 (GAW16), we used the genotype-trait distortion (GTD) scores and proposed analysis procedures to capture the gene-gene interaction effects of multiple susceptibility gene regions on RA. In this paper, we focused on 27 RA candidate gene regions (531 SNPs) based on a literature search. Statistical significance was evaluated using 1000 permutations. HLADRB1 was found to have strong marginal association with RA. We identified 14 significant interactions ( p < 0.01), which were aggregated into an association network among 12 selected candidate genes PADI4 , FCGR3 , TNFRSF1B , ITGAV , BTLA , SLC22A4 , IL3 , VEGF , TNF , NFKBIL1 , TRAF1-C5 , and MIF . Based on our and other contributors' findings during the GAW16 conference, we further studied 24 candidate regions with 336 SNPs. We found 23 significant interactions ( p -value < 0.01), nine interactions in addition to our initial findings, and the association network was extended to include candidate genes HLA-A , HLA-B , HLA-C , CTLA4 , and IL6 . As we will discuss in this paper, the reported possible interactions between genes may suggest potential biological activities of RA.