A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus
Yupeng Li, Richard E Higgs, Robert W Hoffman, Ernst R Dow, Xiong Liu, Michelle Petri, Daniel J Wallace, Thomas Dörner, Brian J Eastwood, Bradley B Miller, Yushi Liu, Yupeng Li, Richard E Higgs, Robert W Hoffman, Ernst R Dow, Xiong Liu, Michelle Petri, Daniel J Wallace, Thomas Dörner, Brian J Eastwood, Bradley B Miller, Yushi Liu
Abstract
Systemic lupus erythematosus (SLE) is a chronic, remitting, and relapsing, inflammatory disease involving multiple organs, which exhibits abnormalities of both the innate and adaptive immune responses. A limited number of transcriptomic studies have characterized the gene pathways involved in SLE in an attempt to identify the key pathogenic drivers of the disease. In order to further advance our understanding of the pathogenesis of SLE, we used a novel Bayesian network algorithm to hybridize knowledge- and data-driven methods, and then applied the algorithm to build an SLE gene network using transcriptomic data from 1,760 SLE patients' RNA from the two tabalumab Phase III trials (ILLUMINATE-I & -II), the largest SLE RNA dataset to date. Further, based on the gene network, we carried out hub- and key driver-gene analyses for gene prioritization. Our analyses identified that the JAK-STAT pathway genes, including JAK2, STAT1, and STAT2, played essential roles in SLE pathogenesis, and reaffirmed the recent discovery of pathogenic relevance of JAK-STAT signaling in SLE. Additionally, we showed that other genes, such as IRF1, IRF7, PDIA4, FAM72C, TNFSF10, DHX58, SIGLEC1, and PML, may be also important in SLE and serve as potential therapeutic targets for SLE. In summary, using a hybridized network construction approach, we systematically investigated gene-gene interactions based on their transcriptomic profiles, prioritized genes based on their importance in the network structure, and revealed new insights into SLE activity.
Trial registration: ClinicalTrials.gov NCT01205438 NCT01196091.
Conflict of interest statement
Thomas Dörner has received grant support from Chugai, Janssen, Novartis, and Sanofi. He has received consultancy support from AbbVie, Celgene, Eli Lilly and Company, Janssen, Novartis, Roche, Samsung, and UCB, and speaker bureau fees from Eli Lilly and Company and Roche. Michelle Petri has received consultancy support from Eli Lilly and Company. Daniel Wallace has received consulting support from Amgen, Eli Lilly and Company, EMD Merck Serono, and Pfizer. Yupeng Li, Richard Higgs, Robert Hoffman, Ernst Dow, Xiong Liu, Brian Eastwood, Bradley Miller and Yushi Liu are employees and stockholders of Eli Lilly and Company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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