Integrative bioinformatics for the discovery of genetic modifiers of bleomycin-induced pulmonary fibrosis

Bleomycin-induced pulmonary fibrosis (BIPF) is a disease caused by the chemotherapeutic bleomycin in which normal lung tissue is replaced with fibrous tissue that is unable to fulfill the normal functions of oxygen exchange in the lung. The development of this disease is dictated, in part, by a set of genes governing susceptibility. Knowledge of such genetic modifiers offers novel therapeutic targets and improved understanding of the pathways involved in the disease process. Our method integrates different data types to identify genes that have a single nucleotide polymorphism (SNP) disrupting a transcription factor binding site that modifies the outcome of BIPF. Our current approach examines over 7 million SNPs, phenotypes from 11 inbred mice strains, mRNA expression data, linkage data, and over 600 transcription factor binding sites from the TRANSFAC database. Each gene is scored with respect to each data type and then integrated using a weighted multiplicative model. Our integrative method produces a list of potential genetic modifiers that will be validated using allelic imbalance tests, existing knockout mice if available, siRNA or antibodies. By investigating these genes, we have identified several that are related to known genetic modifiers or others that make biological sense such as H2-Q2, an antigen presentation gene, and Runx1, a transcription factor known to interact with the known BIPF genetic modifiers Smad3 and Cdkn1a