A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease
| Autor: | William E. Balch, Salvatore Loguercio, Alexandre Rosa Campos, Darren M. Hutt |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Proteomics
0301 basic medicine Cystic Fibrosis Genotype Proteome Computational biology Disease Biology medicine.disease_cause Article 03 medical and health sciences Germline mutation Structural Biology Genetic variation medicine Humans Genetic Predisposition to Disease Precision Medicine Molecular Biology Genetic Association Studies Mutation business.industry Genetic heterogeneity Gene Expression Profiling Genetic Variation Precision medicine 030104 developmental biology Personalized medicine business Biomarkers |
| Zdroj: | Journal of Molecular Biology. 430:2951-2973 |
| ISSN: | 0022-2836 |
| Popis: | The advent of precision medicine for genetic diseases has been hampered by the large number of variants that cause familial and somatic disease, a complexity that is further confounded by the impact of genetic modifiers. To begin to understand differences in onset, progression and therapeutic response that exist among disease-causing variants, we present the proteomic variant approach (ProVarA), a proteomic method that integrates mass spectrometry with genomic tools to dissect the etiology of disease. To illustrate its value, we examined the impact of variation in cystic fibrosis (CF), where 2025 disease-associated mutations in the CF transmembrane conductance regulator (CFTR) gene have been annotated and where individual genotypes exhibit phenotypic heterogeneity and response to therapeutic intervention. A comparative analysis of variant-specific proteomics allows us to identify a number of protein interactions contributing to the basic defects associated with F508del- and G551D-CFTR, two of the most common disease-associated variants in the patient population. We demonstrate that a number of these causal interactions are significantly altered in response to treatment with Vx809 and Vx770, small-molecule therapeutics that respectively target the F508del and G551D variants. ProVarA represents the first comparative proteomic analysis among multiple disease-causing mutations, thereby providing a methodological approach that provides a significant advancement to existing proteomic efforts in understanding the impact of variation in CF disease. We posit that the implementation of ProVarA for any familial or somatic mutation will provide a substantial increase in the knowledge base needed to implement a precision medicine-based approach for clinical management of disease. |
| Databáze: | OpenAIRE |
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