A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450E

A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450E

Wang, L, Li, Y and Zhou, S 2009, 'A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450E', Drug Metabolism and Disposition, vol. 37, no. 5, pp. 977-991.

Document type:	Journal Article
Collection:	Journal Articles

Title	A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450E
Author(s)	Wang, L Li, Y Zhou, S
Year	2009
Journal name	Drug Metabolism and Disposition
Volume number	37
Issue number	5
Start page	977
End page	991
Total pages	15
Publisher	American Society for Pharmacology and Experimental Therapeutics
Abstract	Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease and altered drug response. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment, and conducting individualized pharmacotherapy. Numerous nsSNPs have been found in genes coding for human cytochromes P450 (P450s), but there is poor knowledge on the relationship between the genotype and phenotype of nsSNPs in P450s. We have identified 791 validated nsSNPs in 57 validated human CYP genes from the National Center for Biotechnology Information Database of Single Nucleotide Polymorphism and Swiss-Prot database. Using the polymorphism phenotyping (PolyPhen; http://genetics.bwh.harvard.edu/pph) and sorting intolerant from tolerant (SIFT; http://blocks.fhcrc.org/sift/SIFT.html) algorithms, 39 to 43% of nsSNPs in CYP genes were predicted to have functional impacts on protein function. There was a significant concordance between the predicted results using the SIFT and PolyPhen algorithms. A prediction accuracy analysis found that approximately 70% of nsSNPs were predicted correctly as damaging. Of nsSNPs predicted as deleterious, the prediction scores by the SIFT and PolyPhen algorithms were significantly associated with the numbers of nsSNPs with known phenotype confirmed by benchmarking studies, including site-directed mutagenesis analysis and clinical association studies. These amino acid substitutions are supposed to be the pathogenetic basis for the alteration of P450 enzyme activity and the association with disease susceptivity. This prediction analysis of nsSNPs in human CYP genes would be useful for further genotype-phenotype studies on individual differences in drug clearance and clinical response.
Subject	Genome Structure and Regulation
Keyword(s)	cytochrome P450 algorithm amino acid substitution article bioinformatics controlled study disease predisposition enzyme activity genetic algorithm genetic database human nucleotide sequence phenotype priority journal protein function
Copyright notice	© 2009 by The American Society for Pharmacology and Experimental Therapeutics.
ISSN	0090-9556

Access Statistics:	60 Abstract Views - Detailed Statistics
Created:	Tue, 08 Jun 2010, 13:20:56 EST by Catalyst Administrator - Detailed History