title: Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study.
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.
authors.affiliation: Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lun.yang@gmail.com
authors.forename: Lun
authors.initials: L
authors.lastname: Yang
authors.forename: Kejian
authors.initials: K
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.forename: Heng
authors.initials: H
authors.lastname: Luo
authors.forename: Leming
authors.initials: L
authors.lastname: Shi
authors.forename: Chunling
authors.initials: C
authors.lastname: Wan
authors.forename: Xizhi
authors.initials: X
authors.lastname: Guo
authors.forename: Shengying
authors.initials: S
authors.lastname: Qin
authors.forename: Guang
authors.initials: G
authors.lastname: He
authors.forename: Guoyin
authors.initials: G
authors.lastname: Feng
authors.forename: Lin
authors.initials: L
authors.lastname: He
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced*; D001569:Benzodiazepines / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D003024:Clozapine / Q000009:adverse effects*; D019295:Computational Biology / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced*; D018756:GABA Antagonists / Q000009:adverse effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D000077152:Olanzapine; D025941:Protein Interaction Mapping / Q000379:methods*; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D018756:GABA Antagonists; D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; D017382:Reactive Oxygen Species; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine