Integrating rare genetic variants into pharmacogenetic drug response predictions

Abstract

Background: Variability in genes implicated in drug pharmacokinetics or drug response can modulate treatment efficacy or predispose to adverse drug reactions. Besides common genetic polymorphisms, recent sequencing projects revealed a plethora of rare genetic variants in genes encoding proteins involved in drug metabolism, transport, and response.

Results: To understand the global importance of rare pharmacogenetic gene variants, we mapped the variability in 208 pharmacogenes by analyzing exome sequencing data from 60,706 unrelated individuals and estimated the importance of rare and common genetic variants using a computational prediction framework optimized for pharmacogenetic assessments. Our analyses reveal that rare pharmacogenetic variants were strongly enriched in mutations predicted to cause functional alterations. For more than half of the pharmacogenes, rare variants account for the entire genetic variability. Each individual harbored on average a total of 40.6 putatively functional variants, rare variants accounting for 10.8% of these. Overall, the contribution of rare variants was found to be highly gene- and drug-specific. Using warfarin, simvastatin, voriconazole, olanzapine, and irinotecan as examples, we conclude that rare genetic variants likely account for a substantial part of the unexplained inter-individual differences in drug metabolism phenotypes.

Conclusions: Combined, our data reveal high gene and drug specificity in the contributions of rare variants. We provide a proof-of-concept on how this information can be utilized to pinpoint genes for which sequencing-based genotyping can add important information to predict drug response, which provides useful information for the design of clinical trials in drug development and the personalization of pharmacological treatment.

Keywords: ADME genes; Drug response; Genetic variability; Personalized medicine; Pharmacogenetics.

Fig. 1

The landscape of pharmacogenomic variability. a Pie chart showing the distribution of the identified 69,923 variants across transporters (blue), phase 1 (red) and phase 2 (green) enzymes, and other pharmacogenes (purple). b 57,723 (83%) of the identified 69,923 pharmacogenetic variants were novel as compared to dbSNP release 135. c Violin plots showing the evolutionary constraint on loss-of-function (LoF) alleles. High scores indicate significantly less LoF variants than expected by chance. Details regarding the statistical framework are given in Lek et al. [11]. Violin plots were generated using BoxPlotR [50]. d Of the identified variants, 98.5 and 96.2% were rare (MAF < 1%) or very rare (MAF < 0.1%), respectively, and 51.1% of all variants were only found in a single individual

Fig. 2

Rare genetic variants contribute substantially to pharmacogenomic variability. a The frequency of putatively functional variants is plotted in log scale and indicated as dots connected by the black line for each of the 208 pharmacogenes analyzed (right y-axis). The fraction of this functional variability that is allotted to common (blue) or rare (red) variants is indicated on the left y-axis. Importantly, overall genetic variability as well as the fraction of functional variation that is allotted to rare variants differs considerably between genes. b Rare genetic polymorphisms in pharmacogenes are enriched in variants predicted to cause functional alterations. c Across the 208 ADME genes analyzed, each individual was found to harbor on average 4.4 rare functional variants (frameshift, splice, start-lost, stop-gain, and putatively functional missense variants). Of these, 1.8, 1.7, 0.7, and 0.2 are allotted to transporters, phase 1 and phase 2 enzymes, and other pharmacogenes, respectively

Fig. 3

The relevance of rare genetic variants for warfarin response and simvastatin-related myotoxicity. a Scheme depicting the metabolism and therapeutic action of warfarin. The less potent R-enantiomer of warfarin is metabolized by CYP1A1, CYP1A2, CYP3A, and CYP2C19, whereas the more potent S-enantiomer is inactivated by CYP2C9. Warfarin inhibits the VKOR complex, which reduces vitamin K, an essential factor for the formation of functional coagulation factors. See www.pharmgkb.org/pathway/PA145011113 and www.pharmgkb.org/pathway/PA145011114 for further information. b Overview of the aggregated frequencies of common (MAF ≥ 1%, blue) and rare deleterious genetic variants (MAF < 1%, red) in genes involved in warfarin pharmacokinetics or pharmacodynamics. Values next to the columns indicate the relative contribution of rare genetic variants. c Stacked column plot showing the aggregated frequency of deleterious rare variants of potential relevance for warfarin action. d Scheme depicting metabolites and genetic factors involved in the hepatic uptake, metabolism, and excretion of simvastatin. See www.pharmgkb.org/pathway/PA145011109 for further information. e Overview of the aggregated frequencies of common (MAF ≥ 1%, blue) and rare deleterious genetic variants (MAF < 1%, red) in genes implicated in simvastatin ADME. Values next to the columns indicate the relative contribution of rare genetic variants. f Stacked column plot showing the aggregated frequency of deleterious rare variants of potential relevance for simvastatin pharmacokinetics

Fig. 4

Evaluation of the role of rare genetic variants for voriconazole and olanzapine pharmacokinetics. a Schematic depiction of key events in voriconazole metabolism. See www.pharmgkb.org/pathway/PA166160640 for further information. b Overview of the aggregated frequencies of common (MAF ≥ 1%, blue) and rare deleterious genetic variants (MAF < 1%, red) in genes involved in voriconazole metabolism. Values next to the columns indicate the relative contribution of rare genetic variants. c Stacked column plot showing the aggregated frequency of deleterious rare variants of potential relevance for voriconazole metabolism. d Schematic showing steps involved in the pharmacokinetics of the antipsychotic olanzapine. See www.pharmgkb.org/pathway/PA166165056 for further information. e Overview of the aggregated frequencies of common (MAF ≥ 1%, blue) and rare deleterious genetic variants (MAF < 1%, red) in genes implicated in olanzapine clearance. Values next to the columns indicate the relative contribution of rare genetic variants. f The aggregated frequency of deleterious rare variants of potential relevance for olanzapine metabolism is shown

Fig. 5

Analysis of genetic factors contributing to dose-limiting irinotecan toxicity. a Scheme showing tissue specific involvement of gene products in the irinotecan pathway. See www.pharmgkb.org/pathway/PA2001 for further information. b Overview of the aggregated frequencies of common (MAF ≥ 1%, blue) and rare deleterious genetic variants (MAF < 1%, red) in genes implicated in irinotecan metabolism and transport. Values next to the columns indicate the relative contribution of rare genetic variants. c Stacked column plot showing the aggregated frequency of deleterious rare variants involved in irinotecan ADME