In silico comparative characterization of pharmacogenomic missense variants

Abstract

BackgroundMissense pharmacogenomic (PGx) variants refer to amino acid substitutions that potentially affect the pharmacokinetic (PK) or pharmacodynamic (PD) response to drug therapies. The PGx variants, as compared to disease-associated variants, have not been investigated as deeply. The ability to computationally predict future PGx variants is desirable; however, it is not clear what data sets should be used or what features are beneficial to this end. Hence we carried out a comparative characterization of PGx variants with annotated neutral and disease variants from UniProt, to test the predictive power of sequence conservation and structural information in discriminating these three groups.Results126 PGx variants of high quality from PharmGKB were selected and two data sets were created: one set contained 416 variants with structural and sequence information, and, the other set contained 1,265 variants with sequence information only. In terms of sequence conservation, PGx variants are more conserved than neutral variants and much less conserved than disease variants. A weighted random forest was used to strike a more balanced classification for PGx variants. Generally structural features are helpful in discriminating PGx variant from the other two groups, but still classification of PGx from neutral polymorphisms is much less effective than between disease and neutral variants.ConclusionsWe found that PGx variants are much more similar to neutral variants than to disease variants in the feature space consisting of residue conservation, neighboring residue conservation, number of neighbors, and protein solvent accessibility. Such similarity poses great difficulty in the classification of PGx variants and polymorphisms.

Benchmarking in silico Tools for the Functional Assessment of DNA Variants using a Set of Strictly Pharmacogenetic Variants

“…Indeed, we found that SIFT was better at predicting the neutrality of pharmacogenetic variants than their deleteriousness (Figure 2). Our result concurs with that of a previous study showing that pharmacogenetic variants were almost indistinguishable from harmless DNA changes that occurred throughout the human genome (Li et al 2014).…”

“…Owing to its purported versatility, being effective against both coding and non-coding DNA variants, CADD is steadily gaining popularity in pharmacogenetic research (Bush et al 2016). However, one notable caveat of CADD is that it gives much weight to the influence of purifying selection when assessing the functional relevance of a DNA variant, which may be weak against pharmacogenetic variants and thus somewhat irrelevant (Li et al 2014).…”

Development of the PGx‐Passport: A Panel of Actionable Germline Genetic Variants for Pre‐Emptive Pharmacogenetic Testing

“…Including these variants of unknown effect in the reported results would again provide clinically ambiguous results, and, therefore, we argue to exclude these until methods have been developed that enable accurate prediction of functional effects . Thus, until the effects of these variations on functional effect and subsequent drug response are validated, in silico , in vitro , or in vivo , we are unable to apply the results of testing for these variant alleles in clinical care. However, for some alleles for which the association with drug response is already well‐established, it may be useful to determine these alleles even though the frequency may be low.…”

SNP-SIG 2013: from coding to non-coding - new approaches for genomic variant interpretation

“…The SIG topics covered in this proceedings issue address: the SNP annotation [ 5 ] from functional [ 6 , 7 ] and structural [ 8 , 9 ] perspectives, the prediction of pharmocogenomic variants [ 10 ] and new drug targets [ 11 ], the visualization of transcriptome genetic variants [ 12 ], and human population models to predict the rate of private variants [ 13 ].…”