Comparison of genomic and proteomic data in recurrent airway obstruction affected horses using ingenuity pathway analysis®

Abstract

BackgroundRecurrent airway obstruction (RAO) is a severe chronic respiratory disease affecting horses worldwide, though mostly in the Northern hemisphere. Environmental as well as genetic factors strongly influence the course and prognosis of the disease. Research has been focused on characterization of immunologic factors contributing to inflammatory responses, on genetic linkage analysis, and, more recently, on proteomic analysis of airway secretions from affected horses. The goal of this study was to investigate the interactions between eight candidate genes previously identified in a genetic linkage study and proteins expressed in bronchoalveolar lavage fluid (BALF) collected from healthy and RAO-affected horses. The analysis was carried out with Ingenuity Pathway Analysis® bioinformatics software.ResultsThe gene with the greatest number of indirect interactions with the set of proteins identified is Interleukin 4 Receptor (IL-4R), whose protein has also been detected in BALF. Interleukin 21 receptor and chemokine (C-C motif) ligand 24 also showed a large number of interactions with the group of detected proteins. Protein products of other genes like that of SOCS5, revealed direct interactions with the IL-4R protein. The interacting proteins NOD2, RPS6KA5 and FOXP3 found in several pathways are reported regulators of the NFκB pathway.ConclusionsThe pathways generated with IL-4R highlight possible important intracellular signaling cascades implicating, for instance, NFκB. Furthermore, the proposed interaction between SOCS5 and IL-4R could explain how different genes can lead to identical clinical RAO phenotypes, as observed in two Swiss Warmblood half sibling families because these proteins interact upstream of an important cascade where they may act as a functional unit.

Recurrent respiratory disorders in Polish Konik horses - clinical and laboratory findings

“…Considering the origin of the Polish Konik horse from a small number of progenitors (21), namely their close relationship, a higher incidence of genetic diseases can be suspected. Several studies have demonstrated a predisposition for RAO in families, and it is now proven that this disease has a genetic background (6,(14)(15)(16)18). In offspring the risk of developing recurrent airway obstruction is three times higher, when one parent is affected with this disease, and increases almost five times, when both parents have RAO.…”

Equine asthma: An appropriate, translational and comprehendible terminology?

“…This lack of a universally identified pathogenesis likely stems from both the lack of uniformity in the inciting exposures and genetic diversity within and between the relatively small research herds from which the data were derived and the different methodologies used in these studies. Even in RAO, in which the genetic component of disease susceptibility is well established, there is diversity both in the mode of inheritance and the genetically determined immunological pathways recruited in the face of challenge . The negative impact of such diversity on the ability of the clinician to accurately pigeon‐hole specific lower airway diseases in individual animals within a clinical setting is likely to be of even greater significance.…”

Genetics of upper and lower airway diseases in the horse

“…Molecular pathway analyses (Ingenuity Pathway Analysis) of genomic and proteomic data showed that interactions between IL4R gene products and another candidate gene ( SOCS5 ) could explain how different genes and genotypes can lead to identical clinical RAO phenotypes: these proteins interact upstream of an important cascade involving nuclear factor kappa B (NFκB) . This combined evidence (Table ) – from genetic association and linkage analyses , gene expression studies and molecular pathway exploration – indicates that IL4R is presently the major candidate gene in a subset of RAO‐affected horses with a specific genetic background. Definitive proof is still lacking, however: it is important to note that so far no causal mutation for RAO has been identified in IL4R .…”