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A systems biology network model for genetic association studies of nicotine addiction and treatment.

ABSTRACT: OBJECTIVE:Interpreting genome-scale genetic association data, particularly for complex diseases and phenotypes, requires extensive use of prior knowledge across a broad range of potential biological and environmental influences, spanning many scientific subdisciplines. We suggest that known or hypothesized disease risk factors, and causal mechanisms, can be represented using an ontology, a computational specification of a set of concepts and the relations between them. METHODS:We have integrated the expertise of multiple investigators in nicotine pharmacokinetics and pharmacodynamics, nicotine dependence, and clinical smoking cessation outcomes, and represented this knowledge in an ontology-based network model. Our model spans multiple scales, from molecules, genes and cellular pathways, to complex behavioral phenotypes and even environmental factors. To leverage previous and ongoing work in the field of ontology development, we adopt, expand upon and relate elements from existing ontologies whenever possible. RESULTS:We discuss several applications of our ontology: to support interdisciplinary research by graphically representing a complex scientific theory, to facilitate meta-analysis across different studies, to highlight potential interactions, and to support statistical analysis and causal modeling. We demonstrate that our ontology can focus hypothesis testing on areas supported by current theory. CONCLUSION:We describe how an ontology-based computational representation can be applied to disease risk factors and mechanisms, enabling the use of prior knowledge in large-scale genetic association studies in general. In specific, we have developed an initial Smoking Behavior Risk Ontology to support studies related to the pharmacogenetics of nicotine addiction and treatment.

SUBMITTER: Thomas PD

PROVIDER: S-EPMC6485245 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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A systems biology network model for genetic association studies of nicotine addiction and treatment.

Thomas Paul D PD Mi Huaiyu H Swan Gary E GE Lerman Caryn C Benowitz Neal N Tyndale Rachel F RF Bergen Andrew W AW Conti David V DV

Pharmacogenetics and genomics 20090701 7

<h4>Objective</h4>Interpreting genome-scale genetic association data, particularly for complex diseases and phenotypes, requires extensive use of prior knowledge across a broad range of potential biological and environmental influences, spanning many scientific subdisciplines. We suggest that known or hypothesized disease risk factors, and causal mechanisms, can be represented using an ontology, a computational specification of a set of concepts and the relations between them.<h4>Methods</h4>We ...[more]

PMID: 19525886

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Project description:BACKGROUND:Smoking and tobacco use continue to be the largest preventable causes of death globally. A novel therapeutic approach has recently been proposed: administration of an enzyme that degrades nicotine, the main addictive component of tobacco, minimizing brain exposure and reducing its reinforcing effects. Pre-clinical proof of concept has been previously established through dosing the amine oxidase NicA2 from Pseudomonas putida in rat nicotine self-administration models of addiction. RESULTS:This paper describes efforts towards optimizing NicA2 for potential therapeutic use: enhancing potency, improving its pharmacokinetic profile, and attenuating immunogenicity. Libraries randomizing residues located in all 22 active site positions of NicA2 were screened. 58 single mutations with 2- to 19-fold enhanced catalytic activity compared to wt at 10??M nicotine were identified. A novel nicotine biosensor assay allowed efficient screening of the many primary hits for activity at nicotine concentrations typically found in smokers. 10 mutants with improved activity in rat serum at or below 250?nM were identified. These catalytic improvements translated to increased potency in vivo in the form of further lowering of nicotine blood levels and nicotine accumulation in the brains of Sprague-Dawley rats. Examination of the X-ray crystal structure suggests that these mutants may accelerate the rate limiting re-oxidation of the flavin adenine dinucleotide cofactor by enhancing molecular oxygen's access. PEGylation of NicA2 led to prolonged serum half-life and lowered immunogenicity observed in a human HLA DR4 transgenic mouse model, without impacting nicotine degrading activity. CONCLUSIONS:Systematic mutational analysis of the active site of the nicotine-degrading enzyme NicA2 has yielded 10 variants that increase the catalytic activity and its effects on nicotine distribution in vivo at nicotine plasma concentrations found in smokers. In addition, PEGylation substantially increases circulating half-life and reduces the enzyme's immunogenic potential. Taken together, these results provide a viable path towards generation of a drug candidate suitable for human therapeutic use in treating nicotine addiction.

Dataset Information

A systems biology network model for genetic association studies of nicotine addiction and treatment.

Publications

A systems biology network model for genetic association studies of nicotine addiction and treatment.

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