A genetic variant is defined as an allele carrying variation(s) as compared to the gene reference sequence. The term variant is preferably being used instead of the term mutation, which is reserved for rare variants (<1% frequency). Furthermore, the term polymorphism defined as variations having >1 % frequency in the population, is considered inappropriate due to the large inter-population differences in frequency.
Classical approaches in pharmacogenomics involved genotyping of a predefined panel of a selected number of functionally characterized variants. However, the predefined panel approach was mainly applicable to common variants and may not identify or classify rare variants; broader approaches such as next generation sequencing (NGS) are needed to identify rare variants of functional importance.
Analyses of exomes from >60,000 individuals reveal that every 8th nucleotide in the exome exhibits variation and 50 % of all rare genetic variants were indeed only seen in a single individual of the 60,000 analysed. Furthermore, phenotyping in monozygotic and dizygotic twins has shown that in case of two specific medicinal products, only about 40% of the inherited differences in metabolism could be explained by known gene variants exemplifying the large contribution of unknown rare mutations.
Similar rare variability is seen in receptors e.g. mutations in the Cystic fibrosis transmembrane conductance regulator (CFTR) gene. The current routine analyses of the common allelic variants may thus not predict the full inter-individual variability in PK or PD.
In cases where the inter-individual differences in PK or PD are high and not explained by known genetic variants, it is recommended that genomic DNA sequencing is carried out using broader approaches such as whole exome sequencing (WES) or whole genome sequencing (WGS) with subsequent bioinformatic analyses of sequences in appropriate genomic regions. It is also crucial to define the functionality of the novel genetic variants identified.
If variant and functionality analysis is not immediately feasible, samples from PK or PD outliers should be stored for further exploration in line with recommendation of the ICH E18 guideline on genomic sampling and management of genomic data. The informed consent (for research and
clinical studies) should therefore include the potential for later analysis. Handling of incidental findings or discoveries should also be detailed.
Interethnic Differences in Genetic Variants
Genomic studies should consider inter-ethnic differences in allele frequency and distribution. This is true for the majority of rare variants, as well as common genetic variants in ADME genes, HLA alleles, and genes encoding drug targets.
Rare variants in some populations might be very common in other specific geographical regions. When clinical trials are conducted in specific geographical regions, the regional specific distribution of genetic variants anticipated to influence PK or PD should be accounted in the analysis and conclusions. For guidance relating to extrapolation of data across populations, see ICH Topic E5.
Read also: What is Pharmacogenomics?