The symptoms of complex diseases such as allergy, obesity and cancer
depend on the products of multiple interacting genes. High-throughput
techniques have in fact implicated hundreds of genes. There are also
considerable individual variations. A clinical implication of this
may be inadequate treatment response, which is increasingly recognized
as a cause of increased suffering and cost. Ideally, physicians should
be able to personalize medication based on a few diagnostic markers.
Finding these markers is a formidable challenge. We hypothesize that
translational clinical studies based on high-throughput genomics,
advanced computing and systems biology may help identify markers for
personalized medication in complex diseases. We organize disease-associated
genes in networks that are analyzed in a top-down manner. First, modules
of interacting genes with distinct biological functions are identified.
Then the modules are dissected to find pathways and finally upstream
genes with key regulatory functions. An important focus is to develop
methods to form multi-layer modules that integrate information about
disease-associated changes on the DNA, RNA and protein levels. Since
these levels interact, studies of the different levels can be interactively
used to cross-validate the modules. This involves both genetic and
experimental studies, but the ultimate test of the modules will be
whether they can be used for clinical predictions. For example, changes
in RNA expression may be caused by a SNP in a regulatory region. If so,
the corresponding protein is tried as a marker to personalize medication.
We have chosen allergic rhinitis as a model of complex disease because
it is common, well-defined and readily examined in clinical and experimental
studies. Our methods may be generally applicable to complex diseases.
The PI for this project is Mikael Benson
at the University of Göteborg, Sweden.
Other Co-PIs are Lachlan Coin at the Imperial College of London, UK, Eivind Hovig at the Rikshospitalet, Radiomhospitalet, Norway, and Birthe Sönnichsen at Cenix BioScience GMBH, Dresden, Germany.