Allele definition
Contents
How to obtain PGx allele definitions from literature
PGx alleles are collected and distributed through various channels
- PGx alleles on JSON-LD format from the PharmGKB API
- PGx alleles on Excel-style formats, also accessible through the PharmGKB API (but seems to be hidden from the Swagger documentation)
- PGx alleles as VCF files from PharmVar
PGx allele definitions are given in either GRCh37 or GRCh38 reference coordinates. The process of changing from GRCh37 to GRCh38 for PharmGKB seems to be only partially completed (at least in the JSON-LD data). The allele definitions from the three sources are not always one-to-one, and some background knowledge about why this is, is required. Prefiltering of PharmGKB allele definitions were performed by the University of Tartu as shown in Reisberg et al..
How to define PGx alleles for next generation sequencing
PGx alleles are defined as collections of one or more SNPs, INDELs or structural variants. When a patient is sequenced by next generation sequencing (NGS) we may typically observe more variants than those which are included in any individual PGx allele definitions.
This means that
- Patients may have a large, ambiguous number of matching PGx alleles
- Patients may have additional variants that may modify the effect of a known PGx allele
We illustrate some of the problems that we encountered when trying to match patient haplotypes to the PGx allele definitions, by a four loci PGx gene
The SNP array method
This definition only requires matches for variants explicitly included in PGx allele definitions.
This means that
- Several PGx alleles may match the patient
- But the presence of additional variants will have no effect on reported PGx alleles
The PharmCAT method
This definition requires matches also for variants not explicitly included in PGx allele definitions.
This means that
- Only one PGx allele can exist simultaneously for the same patient
- But whenever we have additional variants, no PGx alleles will be reported
(Note that in practice PharmCAT lets the user decide which allele definitions to use in their NamedAlleleMatcher)
Which definition should we stick to?
| Method | Advantages | Disadvantages |
|---|---|---|
| SNP array method | Compatible with previous SNP array methods. Assigns PGx alleles to the maximum number of patients | Multiple PGx alleles are possible |
| PharmCAT method | One PGx allele per patient | Less compatible with previous SNP array methods. Some patients are no longer assigned to a known PGx allele |