Abstract
In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.
Highlights
Clozapine (CLZ) provides one of the most effective therapeutic treatments for schizophrenia [1]
We proposed an in silico methodology termed as antithesis chemical-protein interactome (CPI), which mimics the differences in the drug-protein interactions of the two drugs across a panel of human proteins. e.g., HSPA1A was identified to be targeted by clozapine not olanzapine
We identified from a 410 protein target set retrospectively that Hsp70 protein as the offtarget of CLZ but not OLZ, and that genes sharing the biological function with HSPA1A (Hsp70’s gene) or acting as neighbors in Human Protein Reference Database (HPRD), a protein-protein interaction (PPI) database, with HSPA1A were found up-regulated in cell lines treated by CLZ
Summary
Clozapine (CLZ) provides one of the most effective therapeutic treatments for schizophrenia [1]. It is classified as an atypical antipsychotic drug because of its binding to serotonergic and dopamine receptors. The identification of the biomarkers for clozapine induced agranulocytosis (CIA) could greatly broaden the usage of this drug. Organizations such as the severe adverse event consortium (SAEC) and Duke University are collaborating on identifying genetic risk factors for CIA via genetic association studies (http://www.genomeweb.com/dxpgx/saec-duke-collaborate-rare-variants-adverse-events-research). Instead of the traditional association study, we proposed an alternative computational methodology to identify the genetic risk factors for CIA, by identifying the known risk genes, explaining the relevant mechanism by observing chemical-protein interactions and providing a ‘‘most likely’’ candidate list [7] for pharmacogenetic and pharmacogenomic studies [8]
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